Fatty acid acetylated salicylates and their uses

PRIORITY

0001This application is a division of U.S. patent application Ser. No. 12/499,779 filed Jul. 8, 2009, which claims the benefit of U.S. Provisional Application No. 61/148,658, filed Jan. 30, 2009, U.S. Provisional Application No. 61/104,363, filed Oct. 10, 2008, U.S. Provisional Application No. 61/104,364, filed Oct. 10, 2008, U.S. Provisional Application No. 61/104,366, filed Oct. 10, 2008, and U.S. Provisional Application No. 61/078,983, filed Jul. 8, 2008. The entire disclosures of those applications are relied on and incorporated into this application by reference.

FIELD OF THE INVENTION

0002The invention relates to Fatty Acid Acetylated Salicylate Derivatives, Fatty Acid Acetylated Diflunisal Derivatives, and Fatty Acid Acetylated Triflusal Derivatives (“Compounds of the Invention”); compositions comprising an effective amount of a Fatty Acid Acetylated Salicylate Derivative, a Fatty Acid Acetylated Diflunisal Derivative, and/or a Fatty Acid Acetylated Triflusal Derivative (“Compound of the Invention”); and methods for treating or preventing an inflammatory disease comprising the administration of an effective amount of a Compound of the invention. All patents, patent applications and publications cited herein are, hereby incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

0003Inflammatory pathways underlie the key pathophysiology of many chronic and acute diseases. Unresolved inflammation is important in many chronic disorders, including, but not limited to, heart disease, atherosclerosis, type 1 and type 2 diabetes, dyslipidemia, asthma, arthritis (including rheumatoid arthritis (RA)), osteoarthritis, cystic fibrosis, muscle wasting disease (including muscular dystrophy), pain, insulin resistance, oxidative stress, inflammatory bowel disease (IBD) (including colitis and Crohn's disease), and neurodegenerative disease (including Alzheimer's disease).

0004In more recent years, the study of inflammation has gone deeper into the cell. Cell-signaling molecules have been identified that modulate the expression of genes that control the inflammatory response, including the pro-inflammatory response and the anti-inflammatory response. One of the central regulators that balance the genes encoding anti- and pro-inflammation factors is Nuclear Factor Kappa Beta (NFκB). NFκB is a family of transcriptions factors that include p50 (NFκB1), p52 (NFκB2), p65 (RelA); c-Rel and RelB. These nuclear factors are held as complexes or dimeric pairs in an inactive state in the cytoplasm as a complex by a NFκB inhibitory factor IκB. The IκB proteins include IκBα, IκBβ, and IκBε, but others also exist. The inactive NFκB complex is released from the cytoplasm by phosphorylation of the IκB protein through kinases such as IKKβ. The kinases regulating NFκB activity are activated by immune responses or cellular stresses. Thus, in the cytoplasmic NFκB complex such as IkB/p65/p50, IkB becomes phosphorylated through kinases such as IKKβ and releases dimeric pairs of NFκB to the nucleus such as p65/p50. In the nucleus, NFκB regulates genetic expression of proinflammatory factors such as cytokines like TNFα, IL-6, and IL-1β in addition to enzymes such as cyclooxygenase-2 (COX-2) one of the enzymes that converts arachidonic acid to prostaglandin H2 (PGH2). These factors induce inflammation in various tissues. In addition, depending upon the cellular context and the NFκB nuclear factors released NFκB can cause the expression of anti-inflammatory genes.

0005Salicylates and other non-steroidal anti-inflammatory drugs (NSAIDs) can influence the NFκB pathway, allowing people to derive relief and reduced inflammation from these drugs. Aspirin and COX inhibitors act to reduce inflammation by reversibly or irreversibly blocking access to the hydrophobic channel via acetylation of serine 530 (COX-1) or Serine 516 (COX-2). For some selective NSAIDs with a carboxylate group, there is significant charge-charge interaction with Arginine 120. This binding or interaction blocks the cyclooxygenase enzyme that forms PGH₂. Salicylate does not irreversibly inhibit cyclooxygenase because it lacks the ability to acylate the COX enzyme and has little, if any, direct inhibitory action on the COX enzyme at concentrations that are relevant in vivo. Salicylate has been shown to inhibit the activity of IKKβ and thereby inhibit NFκB leading to reduced expression of COX-2 in an inflammatory state where COX-2 expression has been induced.

0006Another example of an NSAID is diflunisal:

0007<chemistry id="CHEM-US-00001" num="00001"><img file="US8729293B2_D0001.tif" /></chemistry>

0008Yet another example of an NSAID is triflusal:

0009<chemistry id="CHEM-US-00002" num="00002"><img file="US8729293B2_D0002.tif" /></chemistry>

0010Diflunisal and Triflusal are commonly used to relieve pain, tenderness, swelling and stiffness caused by osteoarthritis and rheumatoid arthritis, and to relieve mild to moderate ain generally.

0011Problems arise in salicylate therapy due to side effects, which means alternative ways need to be developed and pursued to reduce NFκB activity. Some salicylates, when given orally, have a key disadvantage of causing gastric ulcers over the long term in chronic administration. In addition, salicylates can be strong irritants, thought to be caused by the high local concentration of these COX inhibitors. Many of the unwanted effects of aspirin are caused by the inappropriate inhibition of COX or the NFκB pathway. Although NSAIDs inhibit COX and are efficacious anti-inflammatory agents, adverse effects limit their use.

0012Other anti-inflammatory agents that modulate NFκB activity are omega-3 polyunsaturated fatty acids (PUFA). Omega-3 fatty acids also reduce IL-1, which is an activator of NFκB, and increase anti-inflammatory cytokines, such as IL-10, and adipokines, such as adiponectin. Oily cold water fish, such as salmon, trout, herring, and tuna are the source of dietary marine omega-3 fatty acids with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) being the key marine derived omega-3 fatty acids. Leafy green vegetables, and certain beans, nuts or oils, such as soybeans, walnuts, flaxseed, and canola oil, are also rich dietary sources of omega-3 fatty acids.

0013The anti-inflammatory effects of omega-3 fatty acids have been widely studied with positive results for several chronic inflammatory diseases. TNFα and IL-6 are cytokines that increase dramatically during inflammatory processes and are commonly measured as markers of inflammation. Greater intake of omega-3 PUFA has been shown to associate strongly with lower levels of circulating TNFα and IL-6 (Ferrucci et al., 2006). Furthermore, higher intake of omega-3 PUFA has also been associated with increased levels of markers of antiinflammation, including the well-characterized anti-inflammatory cytokine IL-10 (Ferruccci et al, 2006). Animal models of colitis indicate that fish oil decreases colonic damage and inflammation, weight loss, and mortality. Fish oil supplements in patients with IBD have shown to modulate levels of inflammatory mediators and may be beneficial for the induction and maintenance of remission in ulcerative colitis.

0014In the management of RA and other inflammatory conditions, side effects limit the use of NSAIDs. A clinical trial showed that 39 percent of patients with RA supplemented with cod liver oil were able to reduce their daily NSAID requirement by greater than 30 percent. Omega-3 fatty acids have been used to reduce the risk for sudden death caused by cardiac arrhythmias, have been taken as dietary supplements and the ethyl ester of omega-3 fatty acids as a combination therapy is used to treat dyslipidemia.

0015Furthermore, omega-3 fatty acids have been shown to improve insulin sensitivity and glucose tolerance in normoglycemic men and in obese individuals. Omega-3 fatty acids have also been shown to improve insulin resistance in obese and non-obese patients with an inflammatory phenotype. Lipid, glucose and insulin metabolism have been show to be improved in overweight hypertensive subjects through treatment with omega-3 fatty acids.

0016DHA or EPA, C22 and C20 omega-3 fatty acids, are metabolized to active anti-inflammatory metabolites, some of which include resolvins and protectins, and activate various anti-inflammatory pathways.

0017The ability to simultaneously blunt proinflammatory pathways, for example those that affect levels of C-reactive protein (CRP), TNFα and IL-6 cytokines, while stimulating anti-inflammatory pathways by shunting omega-3 fatty acids, such as DHA and EPA, into metabolic pathways that ultimately produce resolvins, protectins and other metabolites that resolve inflammation would be a great benefit in treating the aforementioned diseases. Inflammation could be particularly vulnerable to a two-pronged attack, inhibiting pro-inflammatory pathways and upregulating anti-inflammatory pathways.

SUMMARY OF THE INVENTION

0018The invention is based in part on the discovery of Fatty Acid Acetylated Salicylate Derivatives and their demonstrated effects in the simultaneous upregulation of anti-inflammatory pathways and down regulation of proinflammatory pathways. The invention is also based in part on the discovery of Fatty Acid Acetylated Diflunisal Derivatives and their upregulation of anti-inflammatory pathways and down regulation of proinflammatory pathways. Additionally, the invention is based in part on the discovery of Fatty Acid Acetylated Triflusal Derivatives and their upregulation of anti-inflammatory pathways and down regulation of proinflammatory pathways. These novel compounds are useful in the treatment or prevention of diseases associated with inflammation.

0019Accordingly, in one aspect, compounds of the Formula I are described:

0020<chemistry id="CHEM-US-00003" num="00003"><img file="US8729293B2_D0003.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0021wherein

0022R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0023W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0024----- represents an optional bond that when present requires that Q is null;

0025a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0026b is H, CH₃, C(O)OH, or O—Z;

0027d is H or C(O)OH;

0028each n, o, p, and q is independently 0 or 1;

0029each Z is H or

0030<chemistry id="CHEM-US-00004" num="00004"><img file="US8729293B2_D0004.tif" /></chemistry>

0031with the proviso that there is at least one

0032<chemistry id="CHEM-US-00005" num="00005"><img file="US8729293B2_D0005.tif" /></chemistry>

0033in the compound;

0034each r is independently 2 or 3;

0035each s is independently 5 or 6;

0036each t is independently 0 or 1;

0037Q is null, C(O)CH₃, Z,

0038<chemistry id="CHEM-US-00006" num="00006"><img file="US8729293B2_D0006.tif" /></chemistry>

0039e is H or any one of the side chains of the naturally occurring amino acids;

0040W₃is null, —O—, or —N(R)—;

0041R is H or C₁-C₃alkyl; and

0042T is H, C(O)CH₃, or Z.

0043In another aspect, compounds of the Formula Ia are described:

0044<chemistry id="CHEM-US-00007" num="00007"><img file="US8729293B2_D0007.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0045wherein

0046R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0047r is 2 or 3; and

0048s is 5 or 6.

0049In another aspect compounds of the Formula Ib are described:

0050<chemistry id="CHEM-US-00008" num="00008"><img file="US8729293B2_D0008.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0051wherein

0052R₁, R₂, R₃, R₄, R₁′, R₂′, R₃′, and R₄′ are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0053W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0054a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0055b is H, CH₃, C(O)OH, or O—Z;

0056d is H or C(O)OH; each of n, o, p, and q is independently 0 or 1;

0057each Z is H or

0058<chemistry id="CHEM-US-00009" num="00009"><img file="US8729293B2_D0009.tif" /></chemistry>

0059with the proviso that there is at least one

0060<chemistry id="CHEM-US-00010" num="00010"><img file="US8729293B2_D0010.tif" /></chemistry>

0061in the compound;

0062each r is independently 2 or 3;

0063each s is independently 5 or 6;

0064each t is 0 or 1; and

0065T is H, C(O)CH₃, or Z.

0066In another aspect compounds of the Formula Ic are described:

0067<chemistry id="CHEM-US-00011" num="00011"><img file="US8729293B2_D0011.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, enantiomers, and stereoisomers thereof, <br /> wherein

0068R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0069W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0070a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0071b is H, CH₃, C(O)OH, or O—Z;

0072d is H or C(O)OH;

0073n, o, p, and q are each independently 0 or 1;

0074Z is H, or

0075<chemistry id="CHEM-US-00012" num="00012"><img file="US8729293B2_D0012.tif" /></chemistry>

0076each r is independently 2 or 3;

0077each s is independently 5 or 6; and

0078t is 0 or 1.

0079In another aspect, compounds of the Formula Id are described:

0080<chemistry id="CHEM-US-00013" num="00013"><img file="US8729293B2_D0013.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0081wherein

0082R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0083W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0084a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0085b is H, CH₃, C(O)OH, or O—Z;

0086d is H or C(O)OH;

0087n, o, p, and q are each independently 0 or 1;

0088Z is H, or

0089<chemistry id="CHEM-US-00014" num="00014"><img file="US8729293B2_D0014.tif" /></chemistry>

0090each r is independently 2 or 3;

0091each s is independently 5 or 6; and

0092each t is independently 0 or 1.

0093In another aspect, compounds of the Formula Ie are described:

0094<chemistry id="CHEM-US-00015" num="00015"><img file="US8729293B2_D0015.tif" /></chemistry><br /> and pharmaceutically acceptable, salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0095wherein

0096R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0097each Z is independently H, —C(O)CH₃or

0098<chemistry id="CHEM-US-00016" num="00016"><img file="US8729293B2_D0016.tif" /></chemistry>

0099with the proviso that there is at least one

0100<chemistry id="CHEM-US-00017" num="00017"><img file="US8729293B2_D0017.tif" /></chemistry>

0101in the compound;

0102each r is independently 2 or 3;

0103each s is independently s is 5 or 6; and

0104each t is independently 0 or 1.

0105In another aspect, compounds of the Formula If are described:

0106<chemistry id="CHEM-US-00018" num="00018"><img file="US8729293B2_D0018.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers; and stereoisomers thereof; <br /> wherein

0107R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0108W₁is O, or NH;

0109W₂is null, O, or NH;

0110a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0111b is H, CH₃, C(O)OH, or O—Z;

0112d is H or C(O)OH;

0113Z is H, or

0114<chemistry id="CHEM-US-00019" num="00019"><img file="US8729293B2_D0019.tif" /></chemistry>

0115each o, p, and q is independently 0 or 1;

0116each r is independently 2 or 3;

0117each s is independently 5 or 6; and

0118each t is independently 0 or 1.

0119In another aspect, compounds of the Formula Ig are described:

0120<chemistry id="CHEM-US-00020" num="00020"><img file="US8729293B2_D0020.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0121wherein

0122R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0123W₃is null, O, or NR;

0124R is H or C₁-C₃alkyl;

0125e is H or any one of the side chains of the naturally occurring amino acids;

0126r is 2 or 3; and

0127s is 5 or 6.

0128In another aspect, compounds of the Formula II are described:

0129<chemistry id="CHEM-US-00021" num="00021"><img file="US8729293B2_D0021.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0130wherein

0131R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃-alkyl, and —S(O)₂C₁-C₃alkyl;

0132W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0133----- represents an optional bond that when present requires that Q is then null;

0134a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0135b is H, CH₃, C(O)OH, or O—Z;

0136d is H or C(O)OH;

0137each n, o, p, and q is independently 0 or 1;

0138each Z is H or

0139<chemistry id="CHEM-US-00022" num="00022"><img file="US8729293B2_D0022.tif" /></chemistry>

0140with the proviso that there is at least one

0141<chemistry id="CHEM-US-00023" num="00023"><img file="US8729293B2_D0023.tif" /></chemistry>

0142in the compound;

0143each r is independently 7;

0144each s is independently 3;

0145each t is independently 0 or 1;

0146Q is null, H, C(O)CH₃, Z,

0147<chemistry id="CHEM-US-00024" num="00024"><img file="US8729293B2_D0024.tif" /></chemistry>

0148e is H or any one of the side chains of the naturally occurring amino acids;

0149W₃is null, —O—, or —N(R)—;

0150R is H or C₁-C₃alkyl; and

0151T is H, C(O)CH₃, or Z.

0152In another aspect, compounds of the Formula III are described:

0153<chemistry id="CHEM-US-00025" num="00025"><img file="US8729293B2_D0025.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0154wherein

0155each W₁and W₂are independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0156----- represents an optional bond that when present requires that Q is null;

0157each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0158each b is H, CH₃, C(O)OH, or O—Z;

0159each d is H or C(O)OH;

0160each n, o, p, and q is independently 0 or 1;

0161each Z is H or

0162<chemistry id="CHEM-US-00026" num="00026"><img file="US8729293B2_D0026.tif" /></chemistry>

0163with the proviso that there is at least one

0164<chemistry id="CHEM-US-00027" num="00027"><img file="US8729293B2_D0027.tif" /></chemistry>

0165in the compound;

0166each r is independently 2, 3, or 7;

0167each s is independently 3, 5, or 6;

0168each t is independently 0 or 1;

0169u is 0 or 1;

0170with the proviso that when r is 7, s is 3;

0171Q is null, C(O)CH₃, Z,

0172<chemistry id="CHEM-US-00028" num="00028"><img file="US8729293B2_D0028.tif" /></chemistry>

0173e is H or any one of the side chains of the naturally occurring amino acids;

0174W₃is null, —O—, or —N(R)—;

0175R is H or C₁-C₃alkyl; and

0176T is H, C(O)CH₃, or Z.

0177In yet another aspect, compounds of the Formula Ina are described:

0178<chemistry id="CHEM-US-00029" num="00029"><img file="US8729293B2_D0029.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0179wherein

0180each W₁and W₂are independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0181----- represents an optional bond that when present requires that Q is null;

0182each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0183each b is H, CH₃, C(O)OH, or O—Z;

0184each d is H or C(O)OH;

0185each n, o, p, and q is independently 0 or 1;

0186each Z is H or

0187<chemistry id="CHEM-US-00030" num="00030"><img file="US8729293B2_D0030.tif" /></chemistry>

0188with the proviso that there is at least one

0189<chemistry id="CHEM-US-00031" num="00031"><img file="US8729293B2_D0031.tif" /></chemistry>

0190in the compound;

0191each r is independently 2, 3, or 7;

0192each s is independently 3, 5, or 6;

0193each t is independently 0 or 1;

0194with the proviso that when r is 7, s is 3;

0195each Q is null, H, C(O)CH₃, Z,

0196<chemistry id="CHEM-US-00032" num="00032"><img file="US8729293B2_D0032.tif" /></chemistry>

0197each e is H or any one of the side chains of the naturally occurring amino acids;

0198W₃is null, —O—, or —N(R)—;

0199R is H or C₁-C₃alkyl; and

0200T is H, C(O)CH₃, or Z.

0201In another aspect, compounds of Formula IV are described herein:

0202<chemistry id="CHEM-US-00033" num="00033"><img file="US8729293B2_D0033.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0203wherein

0204W₁and W₂are each independently null, O, or NH;

0205----- represents an optional bond that when present requires that Q is null;

0206a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0207b is H, CH₃, C(O)OH, or O—Z;

0208d is H or C(O)OH;

0209each n, o, p, and q is independently 0 or 1;

0210each Z is H or

0211<chemistry id="CHEM-US-00034" num="00034"><img file="US8729293B2_D0034.tif" /></chemistry>

0212with the proviso that there is at least one

0213<chemistry id="CHEM-US-00035" num="00035"><img file="US8729293B2_D0035.tif" /></chemistry>

0214in the compound;

0215each r is independently 2 or 3;

0216each s is independently 5 or 6;

0217each t is independently 0 or 1;

0218Q is null, C(O)CH₃, Z, or

0219<chemistry id="CHEM-US-00036" num="00036"><img file="US8729293B2_D0036.tif" /></chemistry>

0220e is H, —C(O)OH, or any one of the side chains of the naturally occurring amino acids;

0221W₃is null, —O—, —N(R)—; and

0222R is H or C₁-C₃alkyl.

0223In another aspect, compounds of the Formula IVa are described:

0224<chemistry id="CHEM-US-00037" num="00037"><img file="US8729293B2_D0037.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0225wherein

0226r is 2 or 3; and

0227s is 5 or 6.

0228In another aspect, compounds of the Formula IVb are described:

0229<chemistry id="CHEM-US-00038" num="00038"><img file="US8729293B2_D0038.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, enantiomers, and stereoisomers thereof,

0230wherein

0231W₁and W₂are each independently null, O, or NH;

0232a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0233b is H, CH₃, C(O)OH, or O—Z;

0234d is H or C(O)OH;

0235each n, o, p, and q is independently 0 or 1;

0236Z is H or

0237<chemistry id="CHEM-US-00039" num="00039"><img file="US8729293B2_D0039.tif" /></chemistry>

0238each r is independently 2 or 3;

0239each s is independently 5 or 6; and

0240t is 0 or 1.

0241In another aspect, compounds of the Formula IVc are described:

0242<chemistry id="CHEM-US-00040" num="00040"><img file="US8729293B2_D0040.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0243wherein

0244W₁and W₂are each independently null, O, or NH;

0245a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0246b is H, CH₃, C(O)OH, or O—Z;

0247d is H or C(O)OH;

0248each of n, o, p, and q is independently 0 or 1;

0249each Z is independently null, H, or

0250<chemistry id="CHEM-US-00041" num="00041"><img file="US8729293B2_D0041.tif" /></chemistry>

0251with the proviso that there is at least one

0252<chemistry id="CHEM-US-00042" num="00042"><img file="US8729293B2_D0042.tif" /></chemistry>

0253in the compound;

0254each r is independently 2 or 3;

0255each s is independently 5 or 6; and

0256each t is independently 0 or 1.

0257In another aspect, compounds of the Formula IVd are described:

0258<chemistry id="CHEM-US-00043" num="00043"><img file="US8729293B2_D0043.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0259each Z is independently null, H, or

0260<chemistry id="CHEM-US-00044" num="00044"><img file="US8729293B2_D0044.tif" /></chemistry>

0261with the proviso that there is at least one

0262<chemistry id="CHEM-US-00045" num="00045"><img file="US8729293B2_D0045.tif" /></chemistry>

0263in the compound;

0264each r is independently 2 or 3;

0265each s is independently s is 5 or 6; and

0266each t is independently 0 or 1.

0267In another aspect, compounds of the Formula IVe are described:

0268<chemistry id="CHEM-US-00046" num="00046"><img file="US8729293B2_D0046.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0269wherein

0270W₁is O, or NH;

0271W₂is null, O, or NH;

0272a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0273b is H, CH₃, C(O)OH, or O—Z;

0274d is H or C(O)OH;

0275each o, p, and q is independently 0 or 1;

0276Z is H or

0277<chemistry id="CHEM-US-00047" num="00047"><img file="US8729293B2_D0047.tif" /></chemistry>

0278each r is independently 2 or 3;

0279each s is independently 5 or 6; and

0280each t is independently 0 or 1.

0281In another aspect, compounds of the Formula IVf are described:

0282<chemistry id="CHEM-US-00048" num="00048"><img file="US8729293B2_D0048.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0283e is H, —C(O)OH or any one of the side chains of the naturally occurring amino acids;

0284W₃is null, —O—, —N(R)—; and

0285R is H or C₁-C₃alkyl,

0286r is 2 or 3; and

0287s is 5 or 6.

0288In another aspect, compounds of the Formula IVg are described:

0289<chemistry id="CHEM-US-00049" num="00049"><img file="US8729293B2_D0049.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0290wherein

0291R is H or C₁-C₃alkyl;

0292W₁and W₂are each independently null, O, or NH;

0293a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0294b is H, CH₃, C(O)OH, or O—Z;

0295d is H or C(O)OH;

0296each n, o, p, and q is independently 0 or 1;

0297Z is H or

0298<chemistry id="CHEM-US-00050" num="00050"><img file="US8729293B2_D0050.tif" /></chemistry>

0299each r is independently 2 or 3;

0300each s is independently 5 or 6; and

0301each t is independently 0 or 1.

0302In still another aspect, compounds of the Formula V are described:

0303<chemistry id="CHEM-US-00051" num="00051"><img file="US8729293B2_D0051.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0304wherein

0305W₁and W₂are each independently null, O, or NH;

0306----- represents an optional bond that when present requires that Q is then null;

0307a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0308b is H, CH₃, C(O)OH, or O—Z;

0309d is H or C(O)OH;

0310each n, o, p, and q is independently 0 or 1;

0311each Z is independently null, H, or

0312<chemistry id="CHEM-US-00052" num="00052"><img file="US8729293B2_D0052.tif" /></chemistry>

0313with the proviso that there is at least one

0314<chemistry id="CHEM-US-00053" num="00053"><img file="US8729293B2_D0053.tif" /></chemistry>

0315in the compound;

0316each r is independently 7;

0317each s is independently 3;

0318each t is independently 0 or 1;

0319Q is null, C(O)CH₃, Z, or

0320<chemistry id="CHEM-US-00054" num="00054"><img file="US8729293B2_D0054.tif" /></chemistry>

0321and

0322W₃is null, —O—, —N(R)—;

0323R is H or C₁-C₃alkyl and

0324e is H, —C(O)OH or any one of the side chains of the naturally occurring amino acids.

0325In yet another aspect, compounds of the Formula VI are described:

0326<chemistry id="CHEM-US-00055" num="00055"><img file="US8729293B2_D0055.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0327wherein

0328W₁and W₂are each independently null, O, or NH;

0329----- represents an optional bond that when present requires that Q is null;

0330a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0331b is H, CH₃, C(O)OH, or O—Z;

0332d is H or C(O)OH;

0333each n, o, p, and q is independently 0 or 1;

0334each Z is H or

0335<chemistry id="CHEM-US-00056" num="00056"><img file="US8729293B2_D0056.tif" /></chemistry>

0336with the proviso that there is at least one

0337<chemistry id="CHEM-US-00057" num="00057"><img file="US8729293B2_D0057.tif" /></chemistry>

0338in the compound;

0339each r is independently 0, 1, 2 or 3;

0340each s is independently an integer from 1 to 10;

0341each t is independently 0 or 1;

0342Q is null, C(O)CH₃, Z, or

0343<chemistry id="CHEM-US-00058" num="00058"><img file="US8729293B2_D0058.tif" /></chemistry>

0344e is H, —C(O)OH, or any one of the side chains of the naturally occurring amino acids;

0345W₃is null, —O—, —N(R)—; and

0346R is H or C₁-C₃alkyl.

0347In another aspect, compounds of the Formula VIa are described:

0348<chemistry id="CHEM-US-00059" num="00059"><img file="US8729293B2_D0059.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0349r is 2 or 3; and

0350s is independently 5 or 6.

0351In another aspect, compounds of the Formula VIb are described:

0352<chemistry id="CHEM-US-00060" num="00060"><img file="US8729293B2_D0060.tif" /></chemistry><br /> and pharmaceutically acceptable salts hydrates, solvates, enantiomers, and stereoisomers thereof, <br /> wherein

0353W₁and W₂are each independently null, O, or NH;

0354a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0355b is H, CH₃, C(O)OH, or O—Z;

0356d is H or C(O)OH;

0357each n, o, p, and q is independently 0 or 1;

0358Z is H or

0359<chemistry id="CHEM-US-00061" num="00061"><img file="US8729293B2_D0061.tif" /></chemistry>

0360each r is independently 2 or 3;

0361each s is independently 5 or 6; and

0362each t is independently 0 or 1.

0363In another aspect, compounds of the Formula VIc are described:

0364<chemistry id="CHEM-US-00062" num="00062"><img file="US8729293B2_D0062.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0365W₁and W₂are each independently null, O, or NH;

0366a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0367b is H, CH₃, C(O)OH, or O—Z;

0368d is H or C(O)OH;

0369each of n, o, p, and q is independently 0 or 1;

0370each Z is independently null, H, or

0371<chemistry id="CHEM-US-00063" num="00063"><img file="US8729293B2_D0063.tif" /></chemistry>

0372with the proviso that at least one Z is

0373<chemistry id="CHEM-US-00064" num="00064"><img file="US8729293B2_D0064.tif" /></chemistry>

0374each r is independently 2 or 3;

0375each s is independently 5 or 6; and

0376each t is independently 0 or 1.

0377In another aspect, compounds of the Formula VId are described:

0378<chemistry id="CHEM-US-00065" num="00065"><img file="US8729293B2_D0065.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0379each Z is independently H, —C(O)CH₃or

0380<chemistry id="CHEM-US-00066" num="00066"><img file="US8729293B2_D0066.tif" /></chemistry>

0381with the proviso that at least one Z is

0382<chemistry id="CHEM-US-00067" num="00067"><img file="US8729293B2_D0067.tif" /></chemistry>

0383each r is independently 2 or 3;

0384each s is independently 5 or 6; and

0385each t is independently 0 or 1.

0386In another aspect, compounds of the Formula VIe are described:

0387<chemistry id="CHEM-US-00068" num="00068"><img file="US8729293B2_D0068.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0388W₁is O, or NH;

0389W₂is null, O, or NH;

0390a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0391b is H, CH₃, C(O)OH, or O—Z;

0392d is H or C(O)OH;

0393each o, p, and q is independently 0 or 1;

0394Z is H or

0395<chemistry id="CHEM-US-00069" num="00069"><img file="US8729293B2_D0069.tif" /></chemistry>

0396each r is independently 2 or 3;

0397each s is independently 5 or 6; and

0398t is independently 0 or 1.

0399In another aspect, compounds of the Formula VIf are described:

0400<chemistry id="CHEM-US-00070" num="00070"><img file="US8729293B2_D0070.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0401e is H, —C(O)OH or any one of the side chains of the naturally occurring amino acids;

0402W₃is null, —O—, —N(R)—; and

0403R is H or C₁-C₃alkyl,

0404r is 2 or 3;

0405s is 5 or 6; and

0406t is 0 or 1.

0407In another aspect, compounds of the Formula VIg are described:

0408<chemistry id="CHEM-US-00071" num="00071"><img file="US8729293B2_D0071.tif" /></chemistry><br /> and pharmaceutically acceptable salts; hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0409wherein

0410R is H or C₁-C₃alkyl;

0411W₁and W₂are each independently null, O, or NH;

0412a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0413b is H, CH₃, C(O)OH, or O—Z;

0414d is H or C(O)OH;

0415each n, o, p, and q is independently 0 or 1;

0416Z is H or

0417<chemistry id="CHEM-US-00072" num="00072"><img file="US8729293B2_D0072.tif" /></chemistry>

0418each r is independently 2 or 3;

0419each s is independently 5 or 6; and

0420each t is independently 0 or 1.

0421In another aspect, compounds of the Formula VII are described:

0422<chemistry id="CHEM-US-00073" num="00073"><img file="US8729293B2_D0073.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0423wherein

0424W₁and W₂are each independently null, O, or NH;

0425----- represents an optional bond that when present requires that Q is then null;

0426a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0427b is H, CH₃, C(O)OH, or O—Z;

0428d is H or C(O)OH;

0429each n, o, p, and q is independently 0 or 1;

0430each Z is H or

0431<chemistry id="CHEM-US-00074" num="00074"><img file="US8729293B2_D0074.tif" /></chemistry>

0432with the proviso that there is at least one

0433<chemistry id="CHEM-US-00075" num="00075"><img file="US8729293B2_D0075.tif" /></chemistry>

0434in the compound;

0435each r is independently 7;

0436each s is independently 3;

0437each t is independently 0 or 1;

0438Q is null, C(O)CH₃, Z, or

0439<chemistry id="CHEM-US-00076" num="00076"><img file="US8729293B2_D0076.tif" /></chemistry>

0440and

0441W₃is null, —O—, —N(R)—;

0442R is H or C₁-C₃alkyl; and

0443e is H, —C(O)OH or any one of the side chains of the naturally occurring amino acids.

0444In a further aspect, compounds of the Formula I′ are described:

0445<chemistry id="CHEM-US-00077" num="00077"><img file="US8729293B2_D0077.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0446wherein

0447R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0448W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0449----- represents an optional bond that when present requires that Q is null;

0450a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0451b is H, CH₃, C(O)OH, or O—Z;

0452d is H or C(O)OH;

0453each n, o, p, and q is independently 0 or 1;

0454each Z is H,

0455<chemistry id="CHEM-US-00078" num="00078"><img file="US8729293B2_D0078.tif" /></chemistry>

0456with the proviso that there is at least one

0457<chemistry id="CHEM-US-00079" num="00079"><img file="US8729293B2_D0079.tif" /></chemistry>

0458in the compound;

0459each r is independently 2 or 3;

0460each s is independently 5 or 6;

0461each t is independently 0 or 1;

0462each v is 1 or 2;

0463R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

0464Q is null, C(O)CH₃, Z,

0465<chemistry id="CHEM-US-00080" num="00080"><img file="US8729293B2_D0080.tif" /></chemistry>

0466e is H or any one of the side chains of the naturally occurring amino acids;

0467W₃is null, —O—, or —N(R)—;

0468R is H or C₁-C₃alkyl; and

0469T is H, C(O)CH₃, or Z.

0470In another aspect, compounds of the Formula Ia′ are described:

0471<chemistry id="CHEM-US-00081" num="00081"><img file="US8729293B2_D0081.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0472wherein

0473R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0474s is 5 or 6;

0475v is 1 or 2; and

0476R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl; —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C

0477In another aspect compounds of the Formula Ib′ are described:

0478<chemistry id="CHEM-US-00082" num="00082"><img file="US8729293B2_D0082.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0479R₁, R₂, R₃, R₄, R₁′, R₂′, R₃′, and R₄′ are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0480W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0481a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0482b is H, CH₃, C(O)OH, or O—Z;

0483d is H or C(O)OH;

0484each of n, o, p, and q is independently 0 or 1;

0485each Z is H,

0486<chemistry id="CHEM-US-00083" num="00083"><img file="US8729293B2_D0083.tif" /></chemistry>

0487with the proviso that there is at least one

0488<chemistry id="CHEM-US-00084" num="00084"><img file="US8729293B2_D0084.tif" /></chemistry>

0489in the compound;

0490each r is independently 2 or 3;

0491each s is independently 5 or 6;

0492each t is independently 0 or 1;

0493each v is 1 or 2;

0494R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl; and

0495T is H, C(O)CH₃, or Z.

0496In another aspect compounds of the Formula Ic′ are described:

0497<chemistry id="CHEM-US-00085" num="00085"><img file="US8729293B2_D0085.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, enantiomers, and stereoisomers thereof,

0498wherein

0499R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0500W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0501a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0502b is H, CH₃, C(O)OH, or O—Z;

0503d is H or C(O)OH;

0504n, o, p, and q are each independently 0 or 1;

0505each Z is H,

0506<chemistry id="CHEM-US-00086" num="00086"><img file="US8729293B2_D0086.tif" /></chemistry>

0507with the proviso that there is at least one

0508<chemistry id="CHEM-US-00087" num="00087"><img file="US8729293B2_D0087.tif" /></chemistry>

0509in the compound;

0510each r is independently 2 or 3;

0511each s is independently 5 or 6;

0512each t is independently 0 or 1;

0513each v is 1 or 2; and

0514R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0515In another aspect, compounds of the Formula Id′ are described:

0516<chemistry id="CHEM-US-00088" num="00088"><img file="US8729293B2_D0088.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0517R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0518W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0519a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0520b is H, CH₃, C(O)OH, or O—Z;

0521d is H or C(O)OH;

0522n, o, p, and q are each independently 0 or 1;

0523each Z is H,

0524<chemistry id="CHEM-US-00089" num="00089"><img file="US8729293B2_D0089.tif" /></chemistry>

0525with the proviso that there is at least one

0526<chemistry id="CHEM-US-00090" num="00090"><img file="US8729293B2_D0090.tif" /></chemistry>

0527in the compound;

0528each r is independently 2 or 3;

0529each s is independently 5 or 6;

0530each t is independently 0 or 1;

0531each v is 1 or 2; and

0532R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0533In another aspect, compounds of the Formula Ie′ are described:

0534<chemistry id="CHEM-US-00091" num="00091"><img file="US8729293B2_D0091.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0535R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0536each Z is independently H, —C(O)CH₃,

0537<chemistry id="CHEM-US-00092" num="00092"><img file="US8729293B2_D0092.tif" /></chemistry>

0538with the proviso that there is at least one

0539<chemistry id="CHEM-US-00093" num="00093"><img file="US8729293B2_D0093.tif" /></chemistry>

0540in the compound;

0541each r is independently 2 or 3;

0542each s is independently s is 5 or 6; and

0543each t is independently 0.0 or 1 each v is 1 or 2; and

0544R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0545In another aspect, compounds of the Formula If′ are described:

0546<chemistry id="CHEM-US-00094" num="00094"><img file="US8729293B2_D0094.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0547R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0548W₁is O, or NH;

0549W₂is null, O, or NH;

0550a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0551b is H, CH₃, C(O)OH, or O—Z;

0552d is H or C(O)OH;

0553each o, p, and q is independently 0 or 1;

0554each Z is H,

0555<chemistry id="CHEM-US-00095" num="00095"><img file="US8729293B2_D0095.tif" /></chemistry>

0556with the proviso that there is at least one

0557<chemistry id="CHEM-US-00096" num="00096"><img file="US8729293B2_D0096.tif" /></chemistry>

0558in the compound;

0559each r is independently 2 or 3;

0560each s is independently 5 or 6;

0561each t is independently 0 or 1;

0562each v is 1 or 2;

0563R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl; —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃—N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0564In another aspect, compounds of the Formula Ig′ are described:

0565<chemistry id="CHEM-US-00097" num="00097"><img file="US8729293B2_D0097.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0566R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0567W₃is null, O, or NH;

0568e is H or any one of the side chains of the naturally occurring amino acids;

0569v is 1 or 2;

0570R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl; and

0571s is 5 or 6.

0572In another aspect, compounds of the Formula II′ are described:

0573<chemistry id="CHEM-US-00098" num="00098"><img file="US8729293B2_D0098.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0574wherein

0575R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

0576W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0577----- represents an optional bond that when present requires that Q is then null;

0578a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0579b is H, CH₃, C(O)OH, or O—Z;

0580d is H or C(O)OH;

0581each n, o, p, and q is independently 0 or 1;

0582each Z is H,

0583<chemistry id="CHEM-US-00099" num="00099"><img file="US8729293B2_D0099.tif" /></chemistry>

0584with the proviso that there is at least one

0585<chemistry id="CHEM-US-00100" num="00100"><img file="US8729293B2_D0100.tif" /></chemistry>

0586in the compound;

0587each r is 7;

0588each s is 3;

0589each t is independently 0 or 1;

0590each v is 1 or 2;

0591R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

0592Q is null, C(O)CH₃, Z,

0593<chemistry id="CHEM-US-00101" num="00101"><img file="US8729293B2_D0101.tif" /></chemistry>

0594e is H or any one of the side chains of the naturally occurring amino acids;

0595W₃is null, —O—, or —N(R)—;

0596R is H or C₁-C₃alkyl; and

0597T is H, C(O)CH₃, or Z.

0598In another aspect, compounds of the Formula III′ are described:

0599<chemistry id="CHEM-US-00102" num="00102"><img file="US8729293B2_D0102.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0600wherein

0601each W₁and W₂are independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0602----- represents an optional bond that when present requires that Q is null;

0603each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0604each b is H, CH₃, C(O)OH, or O—Z;

0605each d is H or C(O)OH;

0606each n, o, p, and q is independently 0 or 1;

0607each Z is H,

0608<chemistry id="CHEM-US-00103" num="00103"><img file="US8729293B2_D0103.tif" /></chemistry>

0609with the proviso that there is at least one

0610<chemistry id="CHEM-US-00104" num="00104"><img file="US8729293B2_D0104.tif" /></chemistry>

0611in the compound;

0612each r is independently 2, 3, or 7;

0613each s is independently 3, 5, or 6;

0614each t is independently 0 or 1;

0615each v is 1 or 2;

0616each R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

0617u is 0 or 1;

0618with the proviso that when r is 7, s is 3;

0619Q is null, C(O)CH₃, Z,

0620<chemistry id="CHEM-US-00105" num="00105"><img file="US8729293B2_D0105.tif" /></chemistry>

0621e is H or any one of the side chains of the naturally occurring amino acids;

0622W₃is null, —O—, or —N(R)—;

0623R is H or C₁-C₃alkyl; and

0624T is H, C(O)CH₃, or Z.

0625In yet another aspect, compounds of the Formula IIIa′ are described:

0626<chemistry id="CHEM-US-00106" num="00106"><img file="US8729293B2_D0106.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0627wherein

0628each W₁and W₂are independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

0629----- represents an optional bond that when present requires that Q is null;

0630each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0631each b is H, CH₃, C(O)OH, or O—Z;

0632each d is H or C(O)OH;

0633each n, o, p, and q is independently 0 or 1;

0634each Z is H,

0635<chemistry id="CHEM-US-00107" num="00107"><img file="US8729293B2_D0107.tif" /></chemistry>

0636with the proviso that there is at least one

0637<chemistry id="CHEM-US-00108" num="00108"><img file="US8729293B2_D0108.tif" /></chemistry>

0638in the compound;

0639each r is independently 2, 3, or 7;

0640each s is independently 3, 5, or 6;

0641each t is independently 0 or 1;

0642each v is 1 or 2;

0643each R₅and R₆are independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

0644with the proviso that when r is 7, s is 3;

0645each Q is null, C(O)CH₃, Z,

0646<chemistry id="CHEM-US-00109" num="00109"><img file="US8729293B2_D0109.tif" /></chemistry>

0647each e is H or any one of the side chains of the naturally occurring amino acids;

0648W₃is null, —O—, or —N(R)—;

0649R is H or C₁-C₃alkyl; and

0650T is H, C(O)CH₃, or Z.

0651In another aspect, compounds of Formula IV′ are described herein:

0652<chemistry id="CHEM-US-00110" num="00110"><img file="US8729293B2_D0110.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0653wherein

0654W₁and W₂are each independently null, O, or NH;

0655----- represents an optional bond that when present requires that Q is null;

0656a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0657b is H, CH₃, C(O)OH, or O—Z;

0658d is H or C(O)OH;

0659each n, o, p, and q is independently 0 or 1;

0660each Z is H,

0661<chemistry id="CHEM-US-00111" num="00111"><img file="US8729293B2_D0111.tif" /></chemistry>

0662with the proviso that there is at least one

0663<chemistry id="CHEM-US-00112" num="00112"><img file="US8729293B2_D0112.tif" /></chemistry>

0664in the compound;

0665each r is independently 2 or 3;

0666each s is independently 5 or 6;

0667each t is independently 0 or 1;

0668each v is 1 or 2;

0669R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

0670Q is null, C(O)CH₃, Z, or

0671<chemistry id="CHEM-US-00113" num="00113"><img file="US8729293B2_D0113.tif" /></chemistry>

0672e is H, —C(O)OH, or any one of the side chains of the naturally occurring amino acids;

0673W₃is null, —O—, —N(R)—; and

0674R is H or C₁-C₃alkyl.

0675In another aspect, compounds of the Formula IVa′ are described:

0676<chemistry id="CHEM-US-00114" num="00114"><img file="US8729293B2_D0114.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0677v is 1 or 2;

0678R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl; and

0679s is 5 or 6.

0680In another aspect, compounds of the Formula IVb′ are described:

0681<chemistry id="CHEM-US-00115" num="00115"><img file="US8729293B2_D0115.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, enantiomers, and stereoisomers thereof,

0682wherein

0683W₁and W₂are each independently null, O, or NH;

0684a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0685b is H, CH₃, C(O)OH, or O—Z;

0686d is H or C(O)OH;

0687each n, o, p, and q is independently 0 or 1;

0688each Z is H,

0689<chemistry id="CHEM-US-00116" num="00116"><img file="US8729293B2_D0116.tif" /></chemistry>

0690with the proviso that there is at least one

0691<chemistry id="CHEM-US-00117" num="00117"><img file="US8729293B2_D0117.tif" /></chemistry>

0692in the compound;

0693each r is independently 2 or 3;

0694each s is independently 5 or 6;

0695each t is independently 0 or 1;

0696each v is 1 or 2;

0697R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0698In another aspect, compounds of the Formula IVc′ are described:

0699<chemistry id="CHEM-US-00118" num="00118"><img file="US8729293B2_D0118.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0700W₁and W₂are each independently null, O, or NH;

0701a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0702b is H, CH₃, C(O)OH, or O—Z;

0703d is H or C(O)OH;

0704each of n, o, p, and q is independently 0 or 1;

0705each Z is null, H,

0706<chemistry id="CHEM-US-00119" num="00119"><img file="US8729293B2_D0119.tif" /></chemistry>

0707with the proviso that there is at least one

0708<chemistry id="CHEM-US-00120" num="00120"><img file="US8729293B2_D0120.tif" /></chemistry>

0709in the compound;

0710each r is independently 2 or 3;

0711each s is independently 5 or 6;

0712each t is independently 0 or 1;

0713each v is 1 or 2;

0714R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl; —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0715In another aspect, compounds of the Formula IVd′ are described:

0716<chemistry id="CHEM-US-00121" num="00121"><img file="US8729293B2_D0121.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0717each Z is null, H,

0718<chemistry id="CHEM-US-00122" num="00122"><img file="US8729293B2_D0122.tif" /></chemistry>

0719with the proviso that there is at least one

0720<chemistry id="CHEM-US-00123" num="00123"><img file="US8729293B2_D0123.tif" /></chemistry>

0721in the compound;

0722each r is independently 2 or 3;

0723each s is independently 5 or 6;

0724each t is independently 0 or 1;

0725each v is 1 or 2;

0726R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0727In another aspect, compounds of the Formula IVe′ are described:

0728<chemistry id="CHEM-US-00124" num="00124"><img file="US8729293B2_D0124.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0729W₁is O, or NH;

0730W₂is null, O, or NH;

0731a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0732b is H, CH₃, C(O)OH, or O—Z;

0733d is H or C(O)OH;

0734each o, p, and q is independently 0 or 1;

0735each Z is H,

0736<chemistry id="CHEM-US-00125" num="00125"><img file="US8729293B2_D0125.tif" /></chemistry>

0737with the proviso that there is at least one

0738<chemistry id="CHEM-US-00126" num="00126"><img file="US8729293B2_D0126.tif" /></chemistry>

0739in the compound;

0740each r is independently 2 or 3;

0741each s is independently 5 or 6;

0742each t is independently 0 or 1;

0743each v is 1 or 2;

0744R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0745In another aspect, compounds of the Formula IVf′ are described:

0746<chemistry id="CHEM-US-00127" num="00127"><img file="US8729293B2_D0127.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0747R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

0748e is H, —C(O)OH or any one of the side chains of the naturally occurring amino acids;

0749W₃is null, —O—, —N(R)—; and

0750R is H or C₁-C₃alkyl,

0751v is 1 or 2;

0752s is 5 or 6.

0753In another aspect, compounds of the Formula IVg′ are described:

0754<chemistry id="CHEM-US-00128" num="00128"><img file="US8729293B2_D0128.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0755wherein

0756R is H or C₁-C₃alkyl;

0757W₁and W₂are each independently null, O, or NH;

0758a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0759b is H, CH₃, C(O)OH, or O—Z;

0760d is H or C(O)OH;

0761each n, o, p, and q is independently 0 or 1;

0762each Z is H,

0763<chemistry id="CHEM-US-00129" num="00129"><img file="US8729293B2_D0129.tif" /></chemistry>

0764with the proviso that there is at least one

0765<chemistry id="CHEM-US-00130" num="00130"><img file="US8729293B2_D0130.tif" /></chemistry>

0766in the compound;

0767each r is independently 2 or 3;

0768each s is independently 5 or 6;

0769each t is independently 0 or 1;

0770each v is 1 or 2;

0771R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃—N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0772In still another aspect, compounds of the Formula V′ are described:

0773<chemistry id="CHEM-US-00131" num="00131"><img file="US8729293B2_D0131.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0774W₁and W₂are each independently null, O, or NH;

0775----- represents an optional bond that when present requires that Q is then null;

0776a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0777b is H, CH₃, C(O)OH, or O—Z;

0778d is H or C(O)OH;

0779each n, o, p, and q is independently 0 or 1;

0780each Z is independently null, H,

0781<chemistry id="CHEM-US-00132" num="00132"><img file="US8729293B2_D0132.tif" /></chemistry>

0782with the proviso that there is at least one

0783<chemistry id="CHEM-US-00133" num="00133"><img file="US8729293B2_D0133.tif" /></chemistry>

0784in the compound;

0785each r is independently 7;

0786each s is independently 3;

0787each t is independently 0 or 1;

0788each v is 1 or 2;

0789R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

0790Q is null, C(O)CH₃, Z, or

0791<chemistry id="CHEM-US-00134" num="00134"><img file="US8729293B2_D0134.tif" /></chemistry>

0792W₃is null, —O—, —N(R)—;

0793R is H or C₁-C₃alkyl; and

0794e is H, —C(O)OH or any one of the side chains of the naturally occurring amino acids.

0795In yet another aspect, compounds of the Formula VI′ are described:

0796<chemistry id="CHEM-US-00135" num="00135"><img file="US8729293B2_D0135.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0797wherein

0798W₁and W₂are each independently null, O, or NH;

0799----- represents an optional bond that when present requires that Q is null;

0800a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0801b is H, CH₃, C(O)OH, or O—Z;

0802d is H or C(O)OH;

0803each n, o, p, and q is independently 0 or 1;

0804each Z is H,

0805<chemistry id="CHEM-US-00136" num="00136"><img file="US8729293B2_D0136.tif" /></chemistry>

0806with the proviso that there is at least one

0807<chemistry id="CHEM-US-00137" num="00137"><img file="US8729293B2_D0137.tif" /></chemistry>

0808in the compound;

0809each r is independently 0, 1, 2, or 3;

0810each s is independently an integer from 1 to 10;

0811each t is independently 0 or 1;

0812each v is 1 or 2;

0813R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

0814Q is null, C(O)CH₃, Z, or

0815<chemistry id="CHEM-US-00138" num="00138"><img file="US8729293B2_D0138.tif" /></chemistry>

0816e is H, —C(O)OH, or any one of the side chains of the naturally occurring amino acids;

0817W₃is null, —O—, —N(R)—; and

0818R is H or C₁-C₃alkyl.

0819In another aspect, compounds of the Formula VIa′ are described:

0820<chemistry id="CHEM-US-00139" num="00139"><img file="US8729293B2_D0139.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0821wherein

0822v is 1 or 2; R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl; and

0823s is independently 5 or 6.

0824In another aspect, compounds of the Formula VIb′ are described:

0825<chemistry id="CHEM-US-00140" num="00140"><img file="US8729293B2_D0140.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, enantiomers, and stereoisomers thereof,

0826wherein

0827W₁and W₂are each independently null, O, or NH;

0828a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0829b is H, CH₃, C(O)OH, or O—Z;

0830d is H or C(O)OH;

0831each n, o, p, and q is independently 0 or 1;

0832each Z is H,

0833<chemistry id="CHEM-US-00141" num="00141"><img file="US8729293B2_D0141.tif" /></chemistry>

0834with the proviso that there is at least one

0835<chemistry id="CHEM-US-00142" num="00142"><img file="US8729293B2_D0142.tif" /></chemistry>

0836in the compound;

0837each r is independently 2 or 3;

0838each s is independently 5 or 6;

0839each t is independently 0 or 1;

0840each v is 1 or 2;

0841R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0842In another aspect, compounds of the Formula VIc′ are described:

0843<chemistry id="CHEM-US-00143" num="00143"><img file="US8729293B2_D0143.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0844W₁and W₂are each independently hull, O, or NH;

0845a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0846b is H, CH₃, C(O)OH, or O—Z;

0847d is H or C(O)OH;

0848each of n, o, p, and q is independently 0 or 1;

0849each Z is independently null, H,

0850<chemistry id="CHEM-US-00144" num="00144"><img file="US8729293B2_D0144.tif" /></chemistry>

0851with the proviso that there is at least one

0852<chemistry id="CHEM-US-00145" num="00145"><img file="US8729293B2_D0145.tif" /></chemistry>

0853in the compound;

0854each r is independently 2 or 3;

0855each s is independently 5 or 6;

0856each t is independently 0 or 1;

0857each v is 1 or 2;

0858R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₃-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0859In another aspect, compounds of the Formula VId′ are described:

0860<chemistry id="CHEM-US-00146" num="00146"><img file="US8729293B2_D0146.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0861each Z is independently H,

0862<chemistry id="CHEM-US-00147" num="00147"><img file="US8729293B2_D0147.tif" /></chemistry>

0863with the proviso that there is at least one

0864<chemistry id="CHEM-US-00148" num="00148"><img file="US8729293B2_D0148.tif" /></chemistry>

0865in the compound;

0866each r is independently 2 or 3;

0867each s is independently 5 or 6;

0868each t is independently 0 or 1;

0869each v is 1 or 2;

0870R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0871In another aspect, compounds of the Formula VIe′ are described:

0872<chemistry id="CHEM-US-00149" num="00149"><img file="US8729293B2_D0149.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0873W₁is O, or NH;

0874W₂is null, O, or NH;

0875a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0876b is H, CH₃, C(O)OH, or O—Z;

0877d is H or C(O)OH;

0878each o, p, and q is independently 0 or 1;

0879each Z is H,

0880<chemistry id="CHEM-US-00150" num="00150"><img file="US8729293B2_D0150.tif" /></chemistry>

0881with the proviso that there is at least one

0882<chemistry id="CHEM-US-00151" num="00151"><img file="US8729293B2_D0151.tif" /></chemistry>

0883in the compound;

0884each r is independently 2 or 3;

0885each s is independently 5 or 6;

0886each t is independently 0 or 1;

0887each v is 1 or 2;

0888R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0889In another aspect, compounds of the Formula VII′ are described:

0890<chemistry id="CHEM-US-00152" num="00152"><img file="US8729293B2_D0152.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

0891e is H, —C(O)OH or any one of the side chains of the naturally occurring amino acids;

0892W₃is null, —O—, —N(R)—; and

0893R is H or C₁-C₃alkyl,

0894each v is 1 or 2;

0895R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

0896s is 5 or 6.

0897In another aspect, compounds of the Formula VIg′ are described:

0898<chemistry id="CHEM-US-00153" num="00153"><img file="US8729293B2_D0153.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0899wherein

0900R is H or C₁-C₃alkyl;

0901W₁and W₂are each independently null, O, or NH;

0902a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0903b is H, CH₃, C(O)OH, or O—Z;

0904d is H or C(O)OH;

0905each n, o, p, and q is independently 0 or 1;

0906each Z is H,

0907<chemistry id="CHEM-US-00154" num="00154"><img file="US8729293B2_D0154.tif" /></chemistry>

0908with the proviso that there is at least one

0909<chemistry id="CHEM-US-00155" num="00155"><img file="US8729293B2_D0155.tif" /></chemistry>

0910in the compound;

0911each r is independently 2 or 3;

0912each s is independently 5 or 6;

0913each t is independently 0 or 1;

0914each v is 1 or 2;

0915R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

0916In another aspect, compounds of the Formula VII′ are described:

0917<chemistry id="CHEM-US-00156" num="00156"><img file="US8729293B2_D0156.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0918wherein

0919W₁and W₂are each independently null, O, or NH;

0920----- represents an optional bond that when present requires that Q is then null;

0921a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0922b is H, CH₃, C(O)OH, or O—Z;

0923d is H or C(O)OH;

0924each n, o, p, and q is independently 0 or 1;

0925each Z is H,

0926<chemistry id="CHEM-US-00157" num="00157"><img file="US8729293B2_D0157.tif" /></chemistry>

0927with the proviso that there is at least one

0928<chemistry id="CHEM-US-00158" num="00158"><img file="US8729293B2_D0158.tif" /></chemistry>

0929in the compound;

0930each r is independently 7;

0931each s is independently 3;

0932each t is independently 0 or 1;

0933each v is 1 or 2;

0934R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

0935Q is null, C(O)CH₃, Z, or

0936<chemistry id="CHEM-US-00159" num="00159"><img file="US8729293B2_D0159.tif" /></chemistry><br /> and

0937W₃is null, —O—, —N(R)—;

0938R is H or C₁-C₃alkyl; and

0939e is H, —C(O)OH or any one of the side chains of the naturally occurring amino acids.

0940In any of the above Formulae, any one or more of H may be substituted with a deuterium. It is also understood in any of the above Formulae that a methyl substituent can be substituted with a C₁-C₆alkyl.

0941Also described are pharmaceutical formulations comprising at least one Compound of the Invention.

0942Also described herein are methods of simultaneously up regulating antiinflammation pathways and down regulating proinflammation pathways in a cell by administering to the cell a Compound of the Invention.

0943Also described herein are methods of simultaneously up regulating antiinflammation pathways and down regulating proinflammation pathways in a patient in need thereof, by administering to the patient an effective amount of a Compound of the Invention.

0944Also described herein are methods of treating a disease susceptible to treatment with a Compound of the Invention in a patient in need thereof by administering to the patient an effective amount of a Compound of the Invention.

0945Also described herein are methods of treating diseases associated with inflammation by administering to a patient in need thereof an effective amount of a Compound of the Invention.

0946The invention also includes pharmaceutical compositions that comprise an effective amount of a Compound of the Invention and a pharmaceutically acceptable carrier. The compositions are useful for treating or preventing an inflammatory disease. The invention includes a Compound of the Invention when provided as a pharmaceutically acceptable prodrug, a hydrate, a salt, such as a pharmaceutically acceptable salt, enantiomer, stereoisomer, or mixtures thereof.

0947The details of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

BRIEF DESCRIPTION OF THE FIGURES

0948<figref idref="DRAWINGS">FIG. 1</figref> is a graphic representation of the data showing the effects of a Compound of the Invention on IL-10 levels in 3T3-L1 adipocytes.

0949<figref idref="DRAWINGS">FIG. 2</figref> is a graphic representation of the data showing the effects of a Compound of the Invention on TNFα release.

0950<figref idref="DRAWINGS">FIG. 3</figref> is graphic representation of the data showing the in vivo effects of Compounds of the Invention in an LPS-challenge TNFα mouse model.

DETAILED DESCRIPTION OF THE INVENTION

0951Inflammation is the underlying cause of and pathological contributor to many chronic diseases including type 2 diabetes, rheumatoid arthritis, psoriasis, inflammatory bowel disease, Parkinson's disease, Alzheimer's disease, multiple sclerosis, epilepsy, and cancer, etc. Inflammation is the body's natural protective response to insult, injury and infection. The normal inflammatory process is highly regulated. The process is initiated by a stimulus which leads to the induction of pro-inflammatory pathways. The response persists while the stimulus is present and is turned off during the resolving phase of inflammation. During each of these phases of the inflammatory response different enzymes, receptors, and effectors, are activated and inactivated. If the stimulus persists, chronic inflammation ensues and results in an imbalance in the pro- and anti-inflammatory pathways. Current therapies that target inflammation have been directed in general at single molecular targets or effectors in single pathways. For example, TNFα antibodies, TNFα soluble receptors, COX-2 inhibitors, CCR2 antagonists, p38 inhibitors, etc. target just the pro-inflammatory arm of inflammation. In general these approaches are not disease modifying and are associated with side effects that result from an imbalanced inflammatory response. The simultaneous targeting of both the pro- and anti-inflammatory pathways in the normal inflammatory response provides superior activity in targeting inflammation, disease modifying activity, and a reduced side effect profile. The Compounds of the Invention possess the ability to inhibit pro-inflammatory pathways, while simultaneously activating anti-inflammatory pathways. The simultaneous targeting of these pathways leads to synergistic efficacy and thus the two activities must be delivered to the target cell and/or tissue together.

0952The Compounds of the Invention have been designed to bring together salicylate analogs and omega 3 fatty acids into a single molecular conjugate. Salicylate analogs inhibit the pro-inflammatory pathway through inhibition of NFκB. The omega 3 fatty acids including DHA, EPA, and ALA activate the anti-inflammatory pathway. The Compounds of the Invention thus possess two activities—the ability to blunt pro-inflammatory activity and the ability to activate anti-inflammatory activity. Compounds of the Invention exhibit potent NFκB and TNFα inhibitory activity in a mouse macrophage cell line, RAW264.7, while the individual components, a salicylate analog and a EFA, alone or in combination together, do not. The activity of the Compounds of the Invention is substantially greater than the sum of the components suggesting that the activity induced by the Compounds of the Invention is synergistic.

DEFINITIONS

0953The following definitions are used in connection with the Fatty Acid Acetylated Salicylate Derivatives, the Fatty Acid Acetylated Diflunisal Derivatives, and Fatty Acid Acetylated Triflusal Derivatives:

0954The term “Compound of the Invention” refers to a Fatty Acid Acetylated Salicylate Derivative described herein, wherein Salicylate Derivative includes, without limitation, salicylic acid and substituted salicylates such as aminosalicylic acid, a Fatty Acid Acetylated Diflunisal Derivative described herein, or a Fatty Acid Acetylated Triflusal Derivative described herein. The term “Compounds of the Invention” refers to more than one Compound of the Invention and may be Fatty Acid Acetylated Salicylate Derivatives, Fatty Acid Acetylated Diflunisal Derivatives, Fatty Acid Acetylated Triflusal Derivatives, or some combination thereof. The Compounds of the Invention include any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof.

0955The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

0956The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

0957Unless otherwise specifically defined, the term “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. The substituents can themselves be optionally substituted.

0958“C₁-C₃alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1-3 carbon atoms. Examples of a C₁-C₃alkyl group include, but are not limited to, methyl, ethyl, propyl and isopropyl.

0959“C₁-C₄alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1-4 carbon atoms. Examples of a C₁-C₄alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and tert-butyl.

0960“C₁-C₅alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1-5 carbon atoms. Examples of a C₁-C₅alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.

0961“C₁-C₆alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1-6 carbon atoms. Examples of a C₁-C₆alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and neopentyl.

0962The term “any one of the side chains of the naturally occurring amino acids” as used herein means a side chain of any one of the following amino acids: Isoleucine, Alanine, Leucine, Asparagine, Lysine, Aspartate, Methionine, Cysteine, Phenylalanine, Glutamate, Threonine, Glutamine, Tryptophan, Glycine, Valine, Proline, Arginine, Serine, Histidine, and Tyrosine.

0963The term “fatty acid” as used herein means an omega-3 fatty acid and fatty acids that are metabolized in vivo to omega-3 fatty acids. Non-limiting examples of fatty acids are all-cis-7,10,13-hexadecatrienoic acid, α-linolenic acid (ALA or all-cis-9,12,15-octadecatrienoic acid), stearidonic acid (STD or all-cis-6,9,12,15-octadecatetraenoic acid), eicosatrienoic acid (ETE or all-cis-11,14,17-eicosatrienoic acid), eicosatetraenoic acid (ETA or all-cis-8,11,14,17-eicosatetraenoic acid), eicosapentaenoic, acid (EPA or all-cis-5,8,11,14,17-eicosapentaenoic acid), docosapentaenoic acid (DPA, clupanodonic acid or all-cis-7,10,13,16,19-docosapentaenoic acid), docosahexaenoic acid (DHA or all-cis-4,7,10,13,16,19-docosahexaenoic acid), tetracosapentaenoic acid (all-cis-9,12,15,18,21-docosahexaenoic acid), or tetracosahexaenoic acid (nisinic acid or all-cis-6,9,12,15,18,21-tetracosenoic acid).

0964A “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.

0965The invention also includes pharmaceutical compositions comprising an effective amount of a Compound of the Invention and a pharmaceutically acceptable carrier. The invention includes a Compound of the Invention when provided as a pharmaceutically acceptable prodrug, hydrate, salt, such as a pharmaceutically acceptable salt, enantiomers, stereoisomers, or mixtures thereof.

0966Representative “pharmaceutically acceptable salts” include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

0967An “effective amount” when used in connection with a Compound of the Invention is an amount effective for treating or preventing an inflammatory disease.

0968The term “carrier”, as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.

0969The term “treating” with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating can be curing, improving, or at least partially ameliorating the disorder.

0970The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwised indicated.

0971The term “administer”, “administering”, or “administration” as used in this disclosure refers to either directly administering a compound or pharmaceutically acceptable salt of the compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

0972The term “prodrug,” as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a Compound of the Invention.

0973The following abbreviations are used herein and have the indicated definitions: DCC is dicyclohexylcarbodiimide, CDI is 1,1′-carbonyldiimidazole, EDC is 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride, HEPES is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, SA is salicylic acid, 5-ASA is 5-aminosalicylic acid, SDS is dodecyl sulfate (sodium salt), TNF is tumor necrosis factor, TRIS is Tris(hydroxymethyl)aminomethane, Ts is tosyl(p-toluenesulfonyl), RT is room temperature, and h is hour.

0000Compounds

0974The present invention provides Fatty Acid Acetylated Salicylate Derivatives according to Formula I, Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, Formula II, and Formula III as set forth below. The present invention also provides, a Fatty Acid Acetylated Diflunisal Derivatives according to Formula IV, Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, Formula IVf, Formula IVg, and Formula V, as set forth below. The present invention additionally provides Fatty Acid Acetylated Triflusal Derivatives according to Formula VI, Formula VIa, Formula VIb, Formula VIc, Formula VId, Formula VIe, Formula VIf, Formula VIg, and Formula VII, as set forth below.

0975Described herein are compounds of the Formula I:

0976<chemistry id="CHEM-US-00160" num="00160"><img file="US8729293B2_D0160.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

0977wherein

0000R₁, R₂, R₃, R₄, W₁, W₂, a, b, c, d, e, the symbol -----, Z, n, o, p, q, r, s, t, Q, and T are as defined above for compounds of Formula I.

0978In some embodiments, R₂is Cl or F.

0979In other embodiments, R₃is Cl or F.

0980In some embodiments, W₁is O.

0981In some embodiments, W₂is O.

0982In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

0983In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

0984In some embodiments, ----- represents a bond.

0985In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

0986In some embodiments, b is O—Z, Z is

0987<chemistry id="CHEM-US-00161" num="00161"><img file="US8729293B2_D0161.tif" /></chemistry><br /> and t is 1.

0988In some embodiments, d is C(O)OH.

0989In some embodiments n, o, p, and q are each 1.

0990In some embodiments, n is O.

0991In some embodiments, Z is

0992<chemistry id="CHEM-US-00162" num="00162"><img file="US8729293B2_D0162.tif" /></chemistry>

0993and r is 2.

0994In some embodiments, Z is

0995<chemistry id="CHEM-US-00163" num="00163"><img file="US8729293B2_D0163.tif" /></chemistry>

0996and r is 3.

0997In some embodiments, Z is

0998<chemistry id="CHEM-US-00164" num="00164"><img file="US8729293B2_D0164.tif" /></chemistry>

0999and s is 5.

1000In some embodiments, Z is

1001<chemistry id="CHEM-US-00165" num="00165"><img file="US8729293B2_D0165.tif" /></chemistry>

1002and s is 6.

1003In some embodiments, t is 1.

1004In some embodiments, Q is C(O)CH₃.

1005In some embodiments, Q is, Z.

1006In some embodiments, Q is

1007<chemistry id="CHEM-US-00166" num="00166"><img file="US8729293B2_D0166.tif" /></chemistry>

1008In some embodiments, Q is

1009<chemistry id="CHEM-US-00167" num="00167"><img file="US8729293B2_D0167.tif" /></chemistry>

1010In some embodiments, T is H.

1011In some embodiments, T is C(O)CH₃.

1012In some embodiments, T is Z.

1013In some embodiments, e is any one of the side chains of the naturally occurring amino acids.

1014In some embodiments, e is H.

1015In other illustrative embodiments, compounds of the Formula I are as set forth below:

1016<chemistry id="CHEM-US-00168" num="00168"><img file="US8729293B2_D0168.tif" /></chemistry>

1017Described herein are compounds of the Formula Ia:

1018<chemistry id="CHEM-US-00169" num="00169"><img file="US8729293B2_D0169.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1019R₁, R₂, R₃, R₄, r, and s are as defined above for compounds of Formula Ia.

1020In some embodiments, R₂is Cl or F.

1021In other embodiments, R₃is Cl or F.

1022In some embodiments, r is 2.

1023In some embodiments, r is 3.

1024In some embodiments, s is 5.

1025In some embodiments, s is 6.

1026In some embodiments, t is 1.

1027In other illustrative embodiments, compounds of Formula Ia are as set forth below:

1028<chemistry id="CHEM-US-00170" num="00170"><img file="US8729293B2_D0170.tif" /></chemistry>

1029Described herein are compounds of the Formula

1030<chemistry id="CHEM-US-00171" num="00171"><img file="US8729293B2_D0171.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein <br /> R₁, R₂, R₃, R₄, R₁′, R₂′, R₃′, R₄′ and W₁, W₂, a, c, b, d, n, o, p, q, Z, r, s, t, and T are as defined above for the compounds of Formula

1031In some embodiments, R₂is Cl or F.

1032In other embodiments, R₃is Cl or F.

1033In some embodiments, W₁is O.

1034In some embodiments, W₂is O.

1035In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1036In some embodiments, b is O—Z, Z is

1037<chemistry id="CHEM-US-00172" num="00172"><img file="US8729293B2_D0172.tif" /></chemistry><br /> and t is 1.

1038In some embodiments, d is C(O)OH.

1039In some embodiments n, o, p, and q are each 1.

1040In some embodiments, n is 0.

1041In some embodiments, Z is

1042<chemistry id="CHEM-US-00173" num="00173"><img file="US8729293B2_D0173.tif" /></chemistry>

1043and r is 2.

1044In some embodiments, Z is

1045<chemistry id="CHEM-US-00174" num="00174"><img file="US8729293B2_D0174.tif" /></chemistry>

1046and r is 3.

1047In some embodiments, Z is

1048<chemistry id="CHEM-US-00175" num="00175"><img file="US8729293B2_D0175.tif" /></chemistry>

1049and s is 5.

1050In some embodiments, Z is

1051<chemistry id="CHEM-US-00176" num="00176"><img file="US8729293B2_D0176.tif" /></chemistry>

1052and s is 6.

1053In some embodiments, t is 1.

1054In some embodiments, T is H.

1055In some embodiments, T is C(O)CH₃.

1056In some embodiments, T is Z.

1057In other illustrative embodiments, compounds of Formula Ib are as set forth below:

1058<chemistry id="CHEM-US-00177" num="00177"><img file="US8729293B2_D0177.tif" /></chemistry>

1059In another aspect, compounds of the Formula Ic are described:

1060<chemistry id="CHEM-US-00178" num="00178"><img file="US8729293B2_D0178.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1061R₁, R₂, R₃, R₄, W₁, W₂, a, c, b, d, n, o, p, q, Z, r, s, and t are as defined above for the compounds of the Formula Ic.

1062In some embodiments, R₂is Cl or F.

1063In other embodiments, R₃is Cl or F.

1064In some embodiments, W₁is O.

1065In some embodiments, W₂is O.

1066In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH.

1067In some embodiments, b is O—Z, Z is

1068<chemistry id="CHEM-US-00179" num="00179"><img file="US8729293B2_D0179.tif" /></chemistry><br /> and t is 1.

1069In some embodiments, d is C(O)OH.

1070In some embodiments n, o, p, and q are each 1.

1071In some embodiments, n is 0.

1072In some embodiments, Z is

1073<chemistry id="CHEM-US-00180" num="00180"><img file="US8729293B2_D0180.tif" /></chemistry>

1074and r is 2.

1075In some embodiments, Z is

1076<chemistry id="CHEM-US-00181" num="00181"><img file="US8729293B2_D0181.tif" /></chemistry>

1077and r is 3.

1078In some embodiments, Z is

1079<chemistry id="CHEM-US-00182" num="00182"><img file="US8729293B2_D0182.tif" /></chemistry>

1080and s is 5.

1081In some embodiments, Z is

1082<chemistry id="CHEM-US-00183" num="00183"><img file="US8729293B2_D0183.tif" /></chemistry>

1083and s is 6.

1084In some embodiments, t is 1.

1085In some embodiments, T is H.

1086In some embodiments, T is C(O)CH₃.

1087In some embodiments, T is Z.

1088In other illustrative embodiments, compounds of Formula Ic are as set forth below:

1089<chemistry id="CHEM-US-00184" num="00184"><img file="US8729293B2_D0184.tif" /></chemistry><chemistry id="CHEM-US-00185" num="00185"><img file="US8729293B2_D0185.tif" /></chemistry>

1090In another aspect, compounds of the Formula Id are described:

1091<chemistry id="CHEM-US-00186" num="00186"><img file="US8729293B2_D0186.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1092R₁, R₂, R₃, R₄W₁, W₂, a, b, c, d, n, o, p, q, Z, r, s, and t are as defined above for the compounds of the Formula Id.

1093In some embodiments, R₂is Cl or F.

1094In other embodiments, R₃is Cl or F.

1095In some embodiments, W₁is O.

1096In some embodiments, W₂is O.

1097In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1098In some embodiments, b is O—Z, Z is

1099<chemistry id="CHEM-US-00187" num="00187"><img file="US8729293B2_D0187.tif" /></chemistry><br /> and t is 1.

1100In some embodiments, d is C(O)OH.

1101In some embodiments n, o, p, and q are each 1.

1102In some embodiments, n is 0.

1103In some embodiments, Z is

1104<chemistry id="CHEM-US-00188" num="00188"><img file="US8729293B2_D0188.tif" /></chemistry>

1105and r is 2.

1106In some embodiments, Z is

1107<chemistry id="CHEM-US-00189" num="00189"><img file="US8729293B2_D0189.tif" /></chemistry>

1108and r is 3.

1109In some embodiments, Z is

1110<chemistry id="CHEM-US-00190" num="00190"><img file="US8729293B2_D0190.tif" /></chemistry>

1111and s is 5.

1112In some embodiments, Z is

1113<chemistry id="CHEM-US-00191" num="00191"><img file="US8729293B2_D0191.tif" /></chemistry>

1114and s is 6.

1115In some embodiments, t is 1.

1116In some embodiments, T is H.

1117In some embodiments, T is C(O)CH₃.

1118In some embodiments, T is Z.

1119In other illustrative embodiments, compounds of Formula Id are as set forth below:

1120<chemistry id="CHEM-US-00192" num="00192"><img file="US8729293B2_D0192.tif" /></chemistry><chemistry id="CHEM-US-00193" num="00193"><img file="US8729293B2_D0193.tif" /></chemistry>

1121In another aspect, compounds of the Formula Ie are described:

1122<chemistry id="CHEM-US-00194" num="00194"><img file="US8729293B2_D0194.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1123wherein

1124R₁, R₂, R₃, R₄, Z, r, s, and t are as defined above for the compounds of Formula Ie.

1125In some embodiments, R₂is Cl or F.

1126In other embodiments, R₃is Cl or F.

1127In some embodiments, Z is

1128<chemistry id="CHEM-US-00195" num="00195"><img file="US8729293B2_D0195.tif" /></chemistry>

1129and r is 2.

1130In some embodiments, Z is

1131<chemistry id="CHEM-US-00196" num="00196"><img file="US8729293B2_D0196.tif" /></chemistry>

1132and r is 3.

1133In some embodiments, Z is

1134<chemistry id="CHEM-US-00197" num="00197"><img file="US8729293B2_D0197.tif" /></chemistry>

1135and s is 5.

1136In some embodiments, Z is

1137<chemistry id="CHEM-US-00198" num="00198"><img file="US8729293B2_D0198.tif" /></chemistry>

1138and s is 6.

1139In some embodiments, t is 1.

1140In other illustrative embodiments, compounds of Formula Ie are as set forth below:

1141<chemistry id="CHEM-US-00199" num="00199"><img file="US8729293B2_D0199.tif" /></chemistry>

1142In another aspect, compounds of the Formula If are described:

1143<chemistry id="CHEM-US-00200" num="00200"><img file="US8729293B2_D0200.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1144R₁, R₂, R₃, R₄W₁, W₂, a, b, c, d, Z, o, p, q, r, s, and t are as defined above for the compounds of the Formula If.

1145In some embodiments, R₂is Cl or F.

1146In other embodiments, R₃is Cl or F.

1147In some embodiments, W₁is O.

1148In some embodiments, W₂is O.

1149In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1150In some embodiments, b is O—Z, Z is

1151<chemistry id="CHEM-US-00201" num="00201"><img file="US8729293B2_D0201.tif" /></chemistry><br /> and t is 1.

1152In some embodiments, d is C(O)OH.

1153In some embodiments n, o, p, and q are each 1.

1154In some embodiments, n is 0.

1155In some embodiments, Z is

1156<chemistry id="CHEM-US-00202" num="00202"><img file="US8729293B2_D0202.tif" /></chemistry>

1157and r is 2.

1158In some embodiments, Z is

1159<chemistry id="CHEM-US-00203" num="00203"><img file="US8729293B2_D0203.tif" /></chemistry>

1160and r is 3.

1161In some embodiments, Z is

1162<chemistry id="CHEM-US-00204" num="00204"><img file="US8729293B2_D0204.tif" /></chemistry>

1163and s is 5.

1164In some embodiments, Z is

1165<chemistry id="CHEM-US-00205" num="00205"><img file="US8729293B2_D0205.tif" /></chemistry>

1166and s is 6.

1167In some embodiments, t is 1.

1168In other illustrative embodiments, compounds of Formula If are as set forth below:

1169<chemistry id="CHEM-US-00206" num="00206"><img file="US8729293B2_D0206.tif" /></chemistry>

1170In another aspect, compounds of the Formula Ig are described.

1171<chemistry id="CHEM-US-00207" num="00207"><img file="US8729293B2_D0207.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein <br /> R₁, R₂, R₃, R₄, W₃, R, e, r, and s are as described above for the compounds of Formula Ig.

1172In some embodiments, W₃is O.

1173In some embodiments, e is sec-butyl.

1174In some embodiments, e is any one of the side chains of the naturally occurring amino acids.

1175In some embodiments, r is 2.

1176In some embodiments, r is 3.

1177In some embodiments, s is 5.

1178In some embodiments, s is 6.

1179In some embodiments, t is 1.

1180In other illustrative embodiments, compounds of Formula Ig are as set forth below:

1181<chemistry id="CHEM-US-00208" num="00208"><img file="US8729293B2_D0208.tif" /></chemistry>

1182In another aspect, compounds of the Formula II are described

1183<chemistry id="CHEM-US-00209" num="00209"><img file="US8729293B2_D0209.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1184wherein

0000R₁, R₂, R₃, R₄, W₁, W₂, a, b, c, d, e, the symbol -----, Z, n, o, p, q, r, s, t, Q, and T are as defined above for compounds of Formula II.

1185In some embodiments, R₂is Cl or F. In other embodiments, R₃is Cl or F. In some embodiments, W₁is O. In some embodiments, W₂is O.

1186In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

1187In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

1188In some embodiments, ----- represents a bond. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z and Z is

1189<chemistry id="CHEM-US-00210" num="00210"><img file="US8729293B2_D0210.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1190<chemistry id="CHEM-US-00211" num="00211"><img file="US8729293B2_D0211.tif" /></chemistry><br /> and R is 7. In other embodiments, Z is

1191<chemistry id="CHEM-US-00212" num="00212"><img file="US8729293B2_D0212.tif" /></chemistry><br /> and S is 3. In some embodiments, t is 1. In some embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

1192<chemistry id="CHEM-US-00213" num="00213"><img file="US8729293B2_D0213.tif" /></chemistry>

1193In some embodiments, Q is

1194<chemistry id="CHEM-US-00214" num="00214"><img file="US8729293B2_D0214.tif" /></chemistry>

1195In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In some embodiments, T is Z. In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H.

1196In another aspect, compounds of Formula III are described:

1197<chemistry id="CHEM-US-00215" num="00215"><img file="US8729293B2_D0215.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1198wherein

0000W₁, W₂, -----, a, b, c, d, n, o, p, q, Z, r, s, t, u, Q, T, e, W₃, R are as defined above for compounds of Formula III.

1199In some embodiments, R₂is Cl or F. In other embodiments, R₃is Cl or F. In some embodiments, W₁is O. In some embodiments, W₂is O.

1200In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

1201In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

1202In some embodiments, -----represents a bond. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z and Z is

1203<chemistry id="CHEM-US-00216" num="00216"><img file="US8729293B2_D0216.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1204<chemistry id="CHEM-US-00217" num="00217"><img file="US8729293B2_D0217.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1205<chemistry id="CHEM-US-00218" num="00218"><img file="US8729293B2_D0218.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1206<chemistry id="CHEM-US-00219" num="00219"><img file="US8729293B2_D0219.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1207<chemistry id="CHEM-US-00220" num="00220"><img file="US8729293B2_D0220.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1. In some embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

1208<chemistry id="CHEM-US-00221" num="00221"><img file="US8729293B2_D0221.tif" /></chemistry>

1209In some embodiments, Q is

1210<chemistry id="CHEM-US-00222" num="00222"><img file="US8729293B2_D0222.tif" /></chemistry>

1211In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In some embodiments, T is Z. In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H.

1212In yet another aspect, compounds of the Formula Ina are described:

1213<chemistry id="CHEM-US-00223" num="00223"><img file="US8729293B2_D0223.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1214wherein

1215W₁, W₂, -----, a, b, c, d, n, o, p, q, Z, r, s, t, Q, T, e, W₃, R are as defined above for compounds of Formula IIIa.

1216In some embodiments, W₁is O. In some embodiments, W₂is O.

1217In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

1218In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

1219In some embodiments, ----- represents a bond. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1220<chemistry id="CHEM-US-00224" num="00224"><img file="US8729293B2_D0224.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1221<chemistry id="CHEM-US-00225" num="00225"><img file="US8729293B2_D0225.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1222<chemistry id="CHEM-US-00226" num="00226"><img file="US8729293B2_D0226.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1223<chemistry id="CHEM-US-00227" num="00227"><img file="US8729293B2_D0227.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1224<chemistry id="CHEM-US-00228" num="00228"><img file="US8729293B2_D0228.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1. In some embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

1225<chemistry id="CHEM-US-00229" num="00229"><img file="US8729293B2_D0229.tif" /></chemistry>

1226In some embodiments, W₃is O. In other embodiments, W₃is N(R). In further embodiments, W₃is NH. In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H.

1227In some embodiments, Q is

1228<chemistry id="CHEM-US-00230" num="00230"><img file="US8729293B2_D0230.tif" /></chemistry>

1229In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In some embodiments, T is Z. In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H.

1230In other illustrative embodiments, compounds of Formula III and Ma are as set forth below:

1231<chemistry id="CHEM-US-00231" num="00231"><img file="US8729293B2_D0231.tif" /></chemistry><chemistry id="CHEM-US-00232" num="00232"><img file="US8729293B2_D0232.tif" /></chemistry>

1232Compounds of the Formula IV are also described herein:

1233<chemistry id="CHEM-US-00233" num="00233"><img file="US8729293B2_D0233.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1234wherein W₁, W₂, -----, a, b, c, d n, o, p, q, Z, r, s, t, u, Q, e, W₃, and R are as defined as above for Formula IV.

1235In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH.

1236In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

1237In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

1238In some embodiments, ----- represents a bond. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1239<chemistry id="CHEM-US-00234" num="00234"><img file="US8729293B2_D0234.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1240<chemistry id="CHEM-US-00235" num="00235"><img file="US8729293B2_D0235.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1241<chemistry id="CHEM-US-00236" num="00236"><img file="US8729293B2_D0236.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1242<chemistry id="CHEM-US-00237" num="00237"><img file="US8729293B2_D0237.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1243<chemistry id="CHEM-US-00238" num="00238"><img file="US8729293B2_D0238.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1. In some embodiments, Q is H. In other embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

1244<chemistry id="CHEM-US-00239" num="00239"><img file="US8729293B2_D0239.tif" /></chemistry>

1245In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H. In other embodiments, e is —C(O)OH. In some embodiments, W₃is —NR—. In some embodiments, W₃is O.

1246In another aspect, compounds of the Formula IVa are described:

1247<chemistry id="CHEM-US-00240" num="00240"><img file="US8729293B2_D0240.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1248wherein r and are as defined above for Formula IVa.

1249In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, s is 5. In some embodiments, s is 6.

1250Illustrative compounds of Formula IVa include:

1251<chemistry id="CHEM-US-00241" num="00241"><img file="US8729293B2_D0241.tif" /></chemistry>

1252In another aspect, compounds of the Formula IVb are described:

1253<chemistry id="CHEM-US-00242" num="00242"><img file="US8729293B2_D0242.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, enantiomers, and stereoisomers thereof,

1254wherein W₁, W₂, a, b, c, d n, o, p, q, Z r, s, and t are as defined above for Formula IVb.

1255In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

1256<chemistry id="CHEM-US-00243" num="00243"><img file="US8729293B2_D0243.tif" /></chemistry><br /> and t is 1. In some embodiments, d s C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0.

1257In some embodiments, Z is

1258<chemistry id="CHEM-US-00244" num="00244"><img file="US8729293B2_D0244.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1259<chemistry id="CHEM-US-00245" num="00245"><img file="US8729293B2_D0245.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1260<chemistry id="CHEM-US-00246" num="00246"><img file="US8729293B2_D0246.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1261<chemistry id="CHEM-US-00247" num="00247"><img file="US8729293B2_D0247.tif" /></chemistry><br /> and s is 6. In other embodiments, Z is not H. In some embodiments, t is 1.

1262Illustrative compounds of Formula IVb include:

1263<chemistry id="CHEM-US-00248" num="00248"><img file="US8729293B2_D0248.tif" /></chemistry><chemistry id="CHEM-US-00249" num="00249"><img file="US8729293B2_D0249.tif" /></chemistry>

1264In another aspect, compounds of the Formula IVc are described:

1265<chemistry id="CHEM-US-00250" num="00250"><img file="US8729293B2_D0250.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1266wherein W₁, W₂, a, b, c, d, n, o, p, q, Z, r, s, and t are as defined above for Formula IVc.

1267In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

1268<chemistry id="CHEM-US-00251" num="00251"><img file="US8729293B2_D0251.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1269<chemistry id="CHEM-US-00252" num="00252"><img file="US8729293B2_D0252.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1270<chemistry id="CHEM-US-00253" num="00253"><img file="US8729293B2_D0253.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1271<chemistry id="CHEM-US-00254" num="00254"><img file="US8729293B2_D0254.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1272<chemistry id="CHEM-US-00255" num="00255"><img file="US8729293B2_D0255.tif" /></chemistry><br /> and s is 6. In some embodiments, at most one Z is H. In some embodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. In some embodiments, t is 1.

1273Illustrative compounds of Formula IVc are:

1274<chemistry id="CHEM-US-00256" num="00256"><img file="US8729293B2_D0256.tif" /></chemistry><chemistry id="CHEM-US-00257" num="00257"><img file="US8729293B2_D0257.tif" /></chemistry>

1275In another aspect, compounds of the Formula IVd are described:

1276<chemistry id="CHEM-US-00258" num="00258"><img file="US8729293B2_D0258.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1277wherein Z, r, s, and t are as defined above for Formula IVd.

1278In some embodiments, Z is

1279<chemistry id="CHEM-US-00259" num="00259"><img file="US8729293B2_D0259.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1280<chemistry id="CHEM-US-00260" num="00260"><img file="US8729293B2_D0260.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1281<chemistry id="CHEM-US-00261" num="00261"><img file="US8729293B2_D0261.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1282<chemistry id="CHEM-US-00262" num="00262"><img file="US8729293B2_D0262.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1.

1283In another aspect, compounds of the Formula IVe are described:

1284<chemistry id="CHEM-US-00263" num="00263"><img file="US8729293B2_D0263.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1285wherein W₁, W₂a, b, c, d, o, p, q, Z, r, s, t, and u are as defined above for Formula IVe.

1286In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1287<chemistry id="CHEM-US-00264" num="00264"><img file="US8729293B2_D0264.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1288<chemistry id="CHEM-US-00265" num="00265"><img file="US8729293B2_D0265.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1289<chemistry id="CHEM-US-00266" num="00266"><img file="US8729293B2_D0266.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1290<chemistry id="CHEM-US-00267" num="00267"><img file="US8729293B2_D0267.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1291<chemistry id="CHEM-US-00268" num="00268"><img file="US8729293B2_D0268.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1.

1292An illustrative compound of Formula IVe is:

1293<chemistry id="CHEM-US-00269" num="00269"><img file="US8729293B2_D0269.tif" /></chemistry>

1294In another aspect, compounds of the Formula IVf are described:

1295<chemistry id="CHEM-US-00270" num="00270"><img file="US8729293B2_D0270.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1296wherein e, W₃, R, r, and s are as defined above for Formula IVf.

1297In some embodiments, W₃is O. In some embodiments, e is sec-butyl. In other embodiments, e is —C(O)OH. In still other embodiments, e is H. In some embodiments, W₃is —NR—. In some embodiments, W₃is O. In some embodiments, Z is

1298<chemistry id="CHEM-US-00271" num="00271"><img file="US8729293B2_D0271.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1299<chemistry id="CHEM-US-00272" num="00272"><img file="US8729293B2_D0272.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1300<chemistry id="CHEM-US-00273" num="00273"><img file="US8729293B2_D0273.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1301<chemistry id="CHEM-US-00274" num="00274"><img file="US8729293B2_D0274.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1.

1302Illustrative compounds of Form ula IVf include:

1303<chemistry id="CHEM-US-00275" num="00275"><img file="US8729293B2_D0275.tif" /></chemistry>

1304In another aspect, compounds of the Formula IVg are described:

1305<chemistry id="CHEM-US-00276" num="00276"><img file="US8729293B2_D0276.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1306wherein R, W₁, W₂, a, b, c, d, n, o, p, q, Z, r, s, and t are as defined above for Formula IVg.

1307In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, CH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

1308<chemistry id="CHEM-US-00277" num="00277"><img file="US8729293B2_D0277.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1309<chemistry id="CHEM-US-00278" num="00278"><img file="US8729293B2_D0278.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1310<chemistry id="CHEM-US-00279" num="00279"><img file="US8729293B2_D0279.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1311<chemistry id="CHEM-US-00280" num="00280"><img file="US8729293B2_D0280.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1312<chemistry id="CHEM-US-00281" num="00281"><img file="US8729293B2_D0281.tif" /></chemistry><br /> and s is 6. In some embodiments, at most one Z is H. In some embodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. In some embodiments, t is 1.

1313Illustrative compounds of Formula IVg include:

1314<chemistry id="CHEM-US-00282" num="00282"><img file="US8729293B2_D0282.tif" /></chemistry>

1315In another aspect, compounds of the Formula V are described:

1316<chemistry id="CHEM-US-00283" num="00283"><img file="US8729293B2_D0283.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1317wherein W₁, W₂, -----, Q, a, b, c, d, e, W₃, n, o, p, q, Z, r, s, and t are as defined above for Formula V.

1318In some embodiments, W₁is O. In some embodiments, W₁is NH. In some embodiments, W₂is O. In some embodiments, W₂is NH.

1319In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

1320In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

1321In some embodiments, ----- represents a bond. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1322<chemistry id="CHEM-US-00284" num="00284"><img file="US8729293B2_D0284.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1323<chemistry id="CHEM-US-00285" num="00285"><img file="US8729293B2_D0285.tif" /></chemistry><br /> and r is 7. In some embodiments, Z is

1324<chemistry id="CHEM-US-00286" num="00286"><img file="US8729293B2_D0286.tif" /></chemistry><br /> and s is 3. In some embodiments, t is 1. In some embodiments, Q is C(O)CH₃, In some embodiments, Q is Z. In some embodiments, Q is

1325<chemistry id="CHEM-US-00287" num="00287"><img file="US8729293B2_D0287.tif" /></chemistry>

1326In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H. In other embodiments, e is —C(O)OH. In some embodiments, W₃is —NR—. In some embodiments, W₃is O.

1327Also described herein are compounds of the Formula VI:

1328<chemistry id="CHEM-US-00288" num="00288"><img file="US8729293B2_D0288.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1329wherein W₁, W₂, -----, a, b, c, d n, o, p, q, Z, r, s, t, u, Q, e, W₃, and R are as defined above for Formula VI.

1330In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH.

1331In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

1332In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

1333In some embodiments, ----- represents a bond. In some embodiments, a and c are each independently H; CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1334<chemistry id="CHEM-US-00289" num="00289"><img file="US8729293B2_D0289.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1335<chemistry id="CHEM-US-00290" num="00290"><img file="US8729293B2_D0290.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1336<chemistry id="CHEM-US-00291" num="00291"><img file="US8729293B2_D0291.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1337<chemistry id="CHEM-US-00292" num="00292"><img file="US8729293B2_D0292.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1338<chemistry id="CHEM-US-00293" num="00293"><img file="US8729293B2_D0293.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1. In some embodiments, Q is H. In other embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

1339<chemistry id="CHEM-US-00294" num="00294"><img file="US8729293B2_D0294.tif" /></chemistry>

1340In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H. In other embodiments, e is —C(O)OH. In some embodiments, W₃is —NH—. In some embodiments, W₃is O.

1341In another aspect, compounds of the Formula VIa are described:

1342<chemistry id="CHEM-US-00295" num="00295"><img file="US8729293B2_D0295.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein r and s are as defined above for Formula VIa.

1343In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, s is 5. In some embodiments, s is 6.

1344Illustrative compounds of Formula VIa include:

1345<chemistry id="CHEM-US-00296" num="00296"><img file="US8729293B2_D0296.tif" /></chemistry>

1346In another aspect, compounds of the Formula VIb are described:

1347<chemistry id="CHEM-US-00297" num="00297"><img file="US8729293B2_D0297.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, enantiomers, and stereoisomers thereof, <br /> wherein W₁, W₂, a, b, c, d n, o, p, q, Z r, s, and t are as defined above for Formula VIb.

1348In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

1349<chemistry id="CHEM-US-00298" num="00298"><img file="US8729293B2_D0298.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0.

1350In some embodiments, Z is

1351<chemistry id="CHEM-US-00299" num="00299"><img file="US8729293B2_D0299.tif" /></chemistry><br /> and r is 2. In some embodiments, Z

1352<chemistry id="CHEM-US-00300" num="00300"><img file="US8729293B2_D0300.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1353<chemistry id="CHEM-US-00301" num="00301"><img file="US8729293B2_D0301.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1354<chemistry id="CHEM-US-00302" num="00302"><img file="US8729293B2_D0302.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1.

1355Illustrative compounds of Formula VIb include:

1356<chemistry id="CHEM-US-00303" num="00303"><img file="US8729293B2_D0303.tif" /></chemistry><chemistry id="CHEM-US-00304" num="00304"><img file="US8729293B2_D0304.tif" /></chemistry><chemistry id="CHEM-US-00305" num="00305"><img file="US8729293B2_D0305.tif" /></chemistry>

1357In another aspect, compounds of the Formula VIc are described:

1358<chemistry id="CHEM-US-00306" num="00306"><img file="US8729293B2_D0306.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1359wherein W₁, W₂, a, b, c, d, n, o, p, q, Z, r, s, and t are as defined above for Formula VIc.

1360In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

1361<chemistry id="CHEM-US-00307" num="00307"><img file="US8729293B2_D0307.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1.

1362In some embodiments, n is 0. In some embodiments, Z is

1363<chemistry id="CHEM-US-00308" num="00308"><img file="US8729293B2_D0308.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1364<chemistry id="CHEM-US-00309" num="00309"><img file="US8729293B2_D0309.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1365<chemistry id="CHEM-US-00310" num="00310"><img file="US8729293B2_D0310.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1366<chemistry id="CHEM-US-00311" num="00311"><img file="US8729293B2_D0311.tif" /></chemistry><br /> and s is 6. In some embodiments, at most one Z is H. In some embodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. In some embodiments, t is 1.

1367Illustrative compounds of Formula VIc are:

1368<chemistry id="CHEM-US-00312" num="00312"><img file="US8729293B2_D0312.tif" /></chemistry><chemistry id="CHEM-US-00313" num="00313"><img file="US8729293B2_D0313.tif" /></chemistry>

1369In another aspect, compounds of the Formula VId are described:

1370<chemistry id="CHEM-US-00314" num="00314"><img file="US8729293B2_D0314.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1371wherein Z, r, s, and t are as defined above for Formula VId.

1372In some embodiments, Z is

1373<chemistry id="CHEM-US-00315" num="00315"><img file="US8729293B2_D0315.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1374<chemistry id="CHEM-US-00316" num="00316"><img file="US8729293B2_D0316.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1375<chemistry id="CHEM-US-00317" num="00317"><img file="US8729293B2_D0317.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1376<chemistry id="CHEM-US-00318" num="00318"><img file="US8729293B2_D0318.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1.

1377In another aspect, compounds of the Formula VIe are described:

1378<chemistry id="CHEM-US-00319" num="00319"><img file="US8729293B2_D0319.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1379wherein W₁, W₂, a, b, c, d, o, p, q, Z, r, s, and t, are as defined above for Formula VIe.

1380In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1381<chemistry id="CHEM-US-00320" num="00320"><img file="US8729293B2_D0320.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1.

1382In some embodiments, n is 0. In some embodiments, Z is

1383<chemistry id="CHEM-US-00321" num="00321"><img file="US8729293B2_D0321.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1384<chemistry id="CHEM-US-00322" num="00322"><img file="US8729293B2_D0322.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1385<chemistry id="CHEM-US-00323" num="00323"><img file="US8729293B2_D0323.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1386<chemistry id="CHEM-US-00324" num="00324"><img file="US8729293B2_D0324.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1.

1387An illustrative compound of Formula VIe is:

1388<chemistry id="CHEM-US-00325" num="00325"><img file="US8729293B2_D0325.tif" /></chemistry>

1389In another aspect, compounds of the Formula VIf are described:

1390<chemistry id="CHEM-US-00326" num="00326"><img file="US8729293B2_D0326.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1391wherein e, W₃, R, r, s, and t are as defined above for Formula VIf.

1392In some embodiments, W₃is O. In some embodiments, e is sec-butyl. In other embodiments, e is —C(O)OH. In still other embodiments, e is H. In some embodiments, W₃is —NR—. In some embodiments, W₃is O. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, s is 5. In some embodiments, s is 6. In some embodiments, t is 1.

1393Illustrative compounds of Formula VIf include:

1394<chemistry id="CHEM-US-00327" num="00327"><img file="US8729293B2_D0327.tif" /></chemistry>

1395In another aspect, compounds of the Formula VIg are described:

1396<chemistry id="CHEM-US-00328" num="00328"><img file="US8729293B2_D0328.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1397wherein R, W¹, W², a, b, c, d, n, o, p, q, Z, r, s, and t are as defined above for Formula VIg.

1398In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

1399<chemistry id="CHEM-US-00329" num="00329"><img file="US8729293B2_D0329.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1400<chemistry id="CHEM-US-00330" num="00330"><img file="US8729293B2_D0330.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1401<chemistry id="CHEM-US-00331" num="00331"><img file="US8729293B2_D0331.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1402<chemistry id="CHEM-US-00332" num="00332"><img file="US8729293B2_D0332.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1403<chemistry id="CHEM-US-00333" num="00333"><img file="US8729293B2_D0333.tif" /></chemistry><br /> and s is 6. In some embodiments, at most one Z is H. In some embodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. In some embodiments, t is 1.

1404Illustrative compounds of Formula VIg include:

1405<chemistry id="CHEM-US-00334" num="00334"><img file="US8729293B2_D0334.tif" /></chemistry>

1406In another aspect, compounds of the Formula VII are described:

1407<chemistry id="CHEM-US-00335" num="00335"><img file="US8729293B2_D0335.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1408wherein W₁, W₂, -----, Q, a, c, d, e, W₃, n, o, p, q, Z, r, s, and t are as defined above for Formula VII.

1409In some embodiments, W₁is O. In some embodiments, W₁is NH. In some embodiments, W₂is O. In some embodiments, W₂is NH.

1410In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

1411In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

1412In some embodiments, ----- represents a bond. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1413<chemistry id="CHEM-US-00336" num="00336"><img file="US8729293B2_D0336.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1.

1414In some embodiments, n is 0. In some embodiments, Z is

1415<chemistry id="CHEM-US-00337" num="00337"><img file="US8729293B2_D0337.tif" /></chemistry><br /> and r is 7. In some embodiments, Z is

1416<chemistry id="CHEM-US-00338" num="00338"><img file="US8729293B2_D0338.tif" /></chemistry><br /> and s is 3. In some embodiments, t is 1. In some embodiments, Q is C(O)CH₃, In some embodiments, Q is Z. In some embodiments, Q is

1417<chemistry id="CHEM-US-00339" num="00339"><img file="US8729293B2_D0339.tif" /></chemistry>

1418In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H. In other embodiments, e is —C(O)OH. In some embodiments, W₃is —NR—. In some embodiments, W₃is O.

1419In a further aspect, compounds of the Formula I′ are described:

1420<chemistry id="CHEM-US-00340" num="00340"><img file="US8729293B2_D0340.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1421wherein

1422R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

1423W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

1424----- represents an optional bond that when present requires that Q is null;

1425a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1426b is H, CH₃, C(O)OH, or O—Z;

1427d is H or C(O)OH;

1428each n, o, p, and q is independently 0 or 1;

1429each Z is H,

1430<chemistry id="CHEM-US-00341" num="00341"><img file="US8729293B2_D0341.tif" /></chemistry>

1431with the proviso that there is at least one

1432<chemistry id="CHEM-US-00342" num="00342"><img file="US8729293B2_D0342.tif" /></chemistry>

1433in the compound;

1434each r is independently 2 or 3;

1435each s is independently 5 or 6;

1436each t is independently 0 or 1;

1437each v is 1 or 2;

1438R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

1439Q is null, C(O)CH₃, Z,

1440<chemistry id="CHEM-US-00343" num="00343"><img file="US8729293B2_D0343.tif" /></chemistry>

1441e is H or any one of the side chains of the naturally occurring amino acids;

1442W₃is null, —O—, or —N(R)—;

1443R is H or C₁-C₃alkyl; and

1444T is H, C(O)CH₃, or Z.

1445In some embodiments, R₂is Cl or F. In other embodiments, R₃is Cl or F. In some embodiments, W₁is O. In some embodiments, W₂is o.

1446In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

1447In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

1448In some embodiments, ----- represents a bond. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1449<chemistry id="CHEM-US-00344" num="00344"><img file="US8729293B2_D0344.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1450<chemistry id="CHEM-US-00345" num="00345"><img file="US8729293B2_D0345.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1451<chemistry id="CHEM-US-00346" num="00346"><img file="US8729293B2_D0346.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1452<chemistry id="CHEM-US-00347" num="00347"><img file="US8729293B2_D0347.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1453<chemistry id="CHEM-US-00348" num="00348"><img file="US8729293B2_D0348.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1. <br /> In some embodiments, Z is

1454<chemistry id="CHEM-US-00349" num="00349"><img file="US8729293B2_D0349.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1455<chemistry id="CHEM-US-00350" num="00350"><img file="US8729293B2_D0350.tif" /></chemistry><br /> and s is 3. In some embodiments, Z is

1456<chemistry id="CHEM-US-00351" num="00351"><img file="US8729293B2_D0351.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1457<chemistry id="CHEM-US-00352" num="00352"><img file="US8729293B2_D0352.tif" /></chemistry><br /> and s is 6. In some embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

1458<chemistry id="CHEM-US-00353" num="00353"><img file="US8729293B2_D0353.tif" /></chemistry>

1459In some embodiments, Q is

1460<chemistry id="CHEM-US-00354" num="00354"><img file="US8729293B2_D0354.tif" /></chemistry>

1461In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In some embodiments, T is Z. In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H.

1462In another aspect, compounds of the Formula Ia′ are described:

1463<chemistry id="CHEM-US-00355" num="00355"><img file="US8729293B2_D0355.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1464R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

1465r is 2 or 3;

1466s is 5 or 6;

1467each v is 1 or 2; and

1468R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

1469In some embodiments, R₂is Cl or F. In other embodiments, R₃is Cl or F. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, s is 5. In some embodiments, s is 6. In some embodiments, t is 1. In some embodiments v is 2.

1470In another aspect compounds of the Formula Ib′ are described:

1471<chemistry id="CHEM-US-00356" num="00356"><img file="US8729293B2_D0356.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1472R₁, R₂, R₃, R₄, R₁′, R₂′, R₃′, and R₄′ are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

1473W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

1474a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1475b is H, CH₃, C(O)OH, or O—Z;

1476d is H or C(O)OH;

1477each of n, o, p, and q is independently 0 or 1;

1478each Z is H,

1479<chemistry id="CHEM-US-00357" num="00357"><img file="US8729293B2_D0357.tif" /></chemistry>

1480with the proviso that there is at least one

1481<chemistry id="CHEM-US-00358" num="00358"><img file="US8729293B2_D0358.tif" /></chemistry>

1482in the compound;

1483each r is independently 2 or 3;

1484each s is independently 5 or 6;

1485each t is independently 0 or 1;

1486each v is 1 or 2;

1487R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl; and

1488T is H, C(O)CH₃, or Z.

1489In some embodiments, R₂is Cl or F. In other embodiments, R₃is Cl or F. In some embodiments, W₁is O. In some embodiments, W₂is O. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

1490<chemistry id="CHEM-US-00359" num="00359"><img file="US8729293B2_D0359.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1491<chemistry id="CHEM-US-00360" num="00360"><img file="US8729293B2_D0360.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1492<chemistry id="CHEM-US-00361" num="00361"><img file="US8729293B2_D0361.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1493<chemistry id="CHEM-US-00362" num="00362"><img file="US8729293B2_D0362.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1494<chemistry id="CHEM-US-00363" num="00363"><img file="US8729293B2_D0363.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1. In some embodiments, Z is

1495<chemistry id="CHEM-US-00364" num="00364"><img file="US8729293B2_D0364.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1496<chemistry id="CHEM-US-00365" num="00365"><img file="US8729293B2_D0365.tif" /></chemistry><br /> and s is 3. In some embodiments, Z is

1497<chemistry id="CHEM-US-00366" num="00366"><img file="US8729293B2_D0366.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1498<chemistry id="CHEM-US-00367" num="00367"><img file="US8729293B2_D0367.tif" /></chemistry><br /> and s is 6. In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In some embodiments, T is Z.

1499In another aspect compounds of the Formula Ic′ are described:

1500<chemistry id="CHEM-US-00368" num="00368"><img file="US8729293B2_D0368.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, enantiomers, and stereoisomers thereof, <br /> wherein

1501R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl; W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

1502a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1503b is H, CH₃, C(O)OH, or O—Z;

1504d is H or C(O)OH;

1505n, o, p, and q are each independently 0 or 1;

1506each Z is H,

1507<chemistry id="CHEM-US-00369" num="00369"><img file="US8729293B2_D0369.tif" /></chemistry>

1508with the proviso that there is at least one

1509<chemistry id="CHEM-US-00370" num="00370"><img file="US8729293B2_D0370.tif" /></chemistry>

1510in the compound;

1511each r is independently 2 or 3;

1512each s is independently 5 or 6;

1513each t is independently 0 or 1;

1514each v is 1 or 2; and

1515R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃—N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

1516In some embodiments, R₂is Cl or F. In other embodiments, R₃is Cl or F.

1517In some embodiments, W₁is O. In some embodiments, W₂is O. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

1518<chemistry id="CHEM-US-00371" num="00371"><img file="US8729293B2_D0371.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1519<chemistry id="CHEM-US-00372" num="00372"><img file="US8729293B2_D0372.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1520<chemistry id="CHEM-US-00373" num="00373"><img file="US8729293B2_D0373.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1521<chemistry id="CHEM-US-00374" num="00374"><img file="US8729293B2_D0374.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1522<chemistry id="CHEM-US-00375" num="00375"><img file="US8729293B2_D0375.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1. In some embodiments, Z is

1523<chemistry id="CHEM-US-00376" num="00376"><img file="US8729293B2_D0376.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1524<chemistry id="CHEM-US-00377" num="00377"><img file="US8729293B2_D0377.tif" /></chemistry><br /> and s is 3. In some embodiments, Z is

1525<chemistry id="CHEM-US-00378" num="00378"><img file="US8729293B2_D0378.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1526<chemistry id="CHEM-US-00379" num="00379"><img file="US8729293B2_D0379.tif" /></chemistry><br /> and s is 6.

1527In another aspect, compounds of the Formula Id′ are described:

1528<chemistry id="CHEM-US-00380" num="00380"><img file="US8729293B2_D0380.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1529R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

1530W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

1531a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1532b is H, CH₃, C(O)OH, or O—Z;

1533d is H or C(O)OH;

1534n, o, p, and q are each independently 0 or 1;

1535each Z is H,

1536<chemistry id="CHEM-US-00381" num="00381"><img file="US8729293B2_D0381.tif" /></chemistry>

1537with the proviso that there is at least one

1538<chemistry id="CHEM-US-00382" num="00382"><img file="US8729293B2_D0382.tif" /></chemistry>

1539in the compound;

1540each r is independently 2 or 3;

1541each s is independently 5 or 6;

1542each t is independently 0 or 1;

1543each v is 1 or 2; and

1544R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

1545In some embodiments, R₂is Cl or F. In other embodiments, R₃is Cl or F. In some embodiments, W₁is O. In some embodiments, W₂is O. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

1546<chemistry id="CHEM-US-00383" num="00383"><img file="US8729293B2_D0383.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1547<chemistry id="CHEM-US-00384" num="00384"><img file="US8729293B2_D0384.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1548<chemistry id="CHEM-US-00385" num="00385"><img file="US8729293B2_D0385.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1549<chemistry id="CHEM-US-00386" num="00386"><img file="US8729293B2_D0386.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1550<chemistry id="CHEM-US-00387" num="00387"><img file="US8729293B2_D0387.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

1551<chemistry id="CHEM-US-00388" num="00388"><img file="US8729293B2_D0388.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1552<chemistry id="CHEM-US-00389" num="00389"><img file="US8729293B2_D0389.tif" /></chemistry><br /> and s is 3. In some embodiments, Z is

1553<chemistry id="CHEM-US-00390" num="00390"><img file="US8729293B2_D0390.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1554<chemistry id="CHEM-US-00391" num="00391"><img file="US8729293B2_D0391.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1. In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In some embodiments, T is Z.

1555In another aspect, compounds of the Formula Ie′ are described:

1556<chemistry id="CHEM-US-00392" num="00392"><img file="US8729293B2_D0392.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1557R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

1558each Z is independently H, —C(O)CH₃,

1559<chemistry id="CHEM-US-00393" num="00393"><img file="US8729293B2_D0393.tif" /></chemistry>

1560with the proviso that there is at least one

1561<chemistry id="CHEM-US-00394" num="00394"><img file="US8729293B2_D0394.tif" /></chemistry>

1562in the compound;

1563each r is independently 2 or 3;

1564each s is independently s is 5 or 6; and

1565each t is independently 0 or 1

1566each v is 1 or 2; and

1567R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

1568In some embodiments, R₂is Cl or F. In other embodiments, R₃is Cl or F. In some embodiments, Z is

1569<chemistry id="CHEM-US-00395" num="00395"><img file="US8729293B2_D0395.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1570<chemistry id="CHEM-US-00396" num="00396"><img file="US8729293B2_D0396.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1571<chemistry id="CHEM-US-00397" num="00397"><img file="US8729293B2_D0397.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1572<chemistry id="CHEM-US-00398" num="00398"><img file="US8729293B2_D0398.tif" /></chemistry><br /> and s is 6. In some embodiments, Z

1573<chemistry id="CHEM-US-00399" num="00399"><img file="US8729293B2_D0399.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1574<chemistry id="CHEM-US-00400" num="00400"><img file="US8729293B2_D0400.tif" /></chemistry><br /> and s is 3. In some embodiments, Z is

1575<chemistry id="CHEM-US-00401" num="00401"><img file="US8729293B2_D0401.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1576<chemistry id="CHEM-US-00402" num="00402"><img file="US8729293B2_D0402.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1.

1577In another aspect, compounds of the Formula If′ are described:

1578<chemistry id="CHEM-US-00403" num="00403"><img file="US8729293B2_D0403.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1579R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

1580W₁is O, or NH;

1581W₂is null, O, or NH;

1582a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1583b is H, CH₃, C(O)OH, or O—Z;

1584d is H or C(O)OH;

1585each o, p, and q is independently 0 or 1;

1586each Z is H,

1587<chemistry id="CHEM-US-00404" num="00404"><img file="US8729293B2_D0404.tif" /></chemistry>

1588with the proviso that there is at least one

1589<chemistry id="CHEM-US-00405" num="00405"><img file="US8729293B2_D0405.tif" /></chemistry>

1590in the compound;

1591each r is independently 2 or 3;

1592each s is independently 5 or 6;

1593each t is independently 0 or 1;

1594each v is 1 or 2;

1595R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

1596In some embodiments, R₂is Cl or F. In other embodiments, R₃is Cl or F. In some embodiments, W₁is O. In some embodiments, W₂is O. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1597<chemistry id="CHEM-US-00406" num="00406"><img file="US8729293B2_D0406.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1598<chemistry id="CHEM-US-00407" num="00407"><img file="US8729293B2_D0407.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1599<chemistry id="CHEM-US-00408" num="00408"><img file="US8729293B2_D0408.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1600<chemistry id="CHEM-US-00409" num="00409"><img file="US8729293B2_D0409.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1601<chemistry id="CHEM-US-00410" num="00410"><img file="US8729293B2_D0410.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

1602<chemistry id="CHEM-US-00411" num="00411"><img file="US8729293B2_D0411.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1603<chemistry id="CHEM-US-00412" num="00412"><img file="US8729293B2_D0412.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1604<chemistry id="CHEM-US-00413" num="00413"><img file="US8729293B2_D0413.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1605<chemistry id="CHEM-US-00414" num="00414"><img file="US8729293B2_D0414.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1.

1606In another aspect, compounds of the Formula Ig′ are described:

1607<chemistry id="CHEM-US-00415" num="00415"><img file="US8729293B2_D0415.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1608R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

1609W₃is null, O, or NH;

1610e is H or any one of the side chains of the naturally occurring amino acids;

1611each v is 1 or 2;

1612R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl; and

1613s is 5 or 6.

1614In some embodiments, W₃is O. In some embodiments, e is sec-butyl. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, s is 5. In some embodiments, s is 6. In some embodiments, t is 1.

1615In another aspect, compounds of the Formula II′ are described:

1616<chemistry id="CHEM-US-00416" num="00416"><img file="US8729293B2_D0416.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1617R₁, R₂, R₃, and R₄are each independently selected from the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃alkyl), —N(C₁—O₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —C(O)H, —C(O)C₁-C₃alkyl, —C(O)OC₁-C₃alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃alkyl), —C(O)N(C₁-C₃alkyl)₂, —C₁-C₃alkyl, —O—C₁-C₃alkyl, —S(O)C₁-C₃alkyl, and —S(O)₂C₁-C₃alkyl;

1618W₁and W₂are each independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

1619----- represents an optional bond that when present requires that Q is then null;

1620a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1621b is H, CH₃, C(O)OH, or O—Z;

1622d is H or C(O)OH;

1623each n, o, p, and q is independently 0 or 1;

1624each Z is H,

1625<chemistry id="CHEM-US-00417" num="00417"><img file="US8729293B2_D0417.tif" /></chemistry>

1626with the proviso that there is at least one

1627<chemistry id="CHEM-US-00418" num="00418"><img file="US8729293B2_D0418.tif" /></chemistry>

1628in the compound;

1629each r is 7;

1630each s is 3;

1631each t is independently 0 or 1;

1632each v is 1 or 2;

1633R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

1634Q is null, H, C(O)CH₃, Z,

1635<chemistry id="CHEM-US-00419" num="00419"><img file="US8729293B2_D0419.tif" /></chemistry>

1636e is H or any one of the side chains of the naturally occurring amino acids;

1637W₃is null, —O—, or —N(R)—;

1638R is H or C₁-C₃alkyl; and

1639T is H, C(O)CH₃, or Z.

1640In some embodiments, R₂is Cl or F. In other embodiments, R₃is Cl or F. In some embodiments, W₁is O. In some embodiments, W₂is O.

1641In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

1642In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

1643In some embodiments, ----- represents a bond. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1644<chemistry id="CHEM-US-00420" num="00420"><img file="US8729293B2_D0420.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1645<chemistry id="CHEM-US-00421" num="00421"><img file="US8729293B2_D0421.tif" /></chemistry><br /> and r is 7. In some embodiments, Z is

1646<chemistry id="CHEM-US-00422" num="00422"><img file="US8729293B2_D0422.tif" /></chemistry><br /> and s is 3. In some embodiments, Z is

1647<chemistry id="CHEM-US-00423" num="00423"><img file="US8729293B2_D0423.tif" /></chemistry><br /> and r is 7. In some embodiments, Z is

1648<chemistry id="CHEM-US-00424" num="00424"><img file="US8729293B2_D0424.tif" /></chemistry><br /> and s is 3. In some embodiments, t is 1. In some embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

1649<chemistry id="CHEM-US-00425" num="00425"><img file="US8729293B2_D0425.tif" /></chemistry>

1650In some embodiments, Q is

1651<chemistry id="CHEM-US-00426" num="00426"><img file="US8729293B2_D0426.tif" /></chemistry>

1652In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In some embodiments, T is Z. In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H.

1653In another aspect, compounds of the Formula III′ are described:

1654<chemistry id="CHEM-US-00427" num="00427"><img file="US8729293B2_D0427.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1655wherein

1656each W₁and W₂are independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

1657----- represents an optional bond that when present requires that Q is null;

1658each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1659each b is H, CH₃, C(O)OH, or O—Z;

1660each d is H or C(O)OH;

1661each n, o, p, and q is independently 0 or 1;

1662each Z is H,

1663<chemistry id="CHEM-US-00428" num="00428"><img file="US8729293B2_D0428.tif" /></chemistry>

1664with the proviso that there is at least one

1665<chemistry id="CHEM-US-00429" num="00429"><img file="US8729293B2_D0429.tif" /></chemistry>

1666in the compound;

1667each r is independently 2, 3, or 7;

1668each s is independently 3, 5, or 6;

1669each t is independently 0 or 1;

1670each v is 1 or 2;

1671each R₅and R₆are independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

1672u is 0 or 1;

1673with the proviso that when r is 7, s is 3;

1674Q is null, C(O)CH₃, Z,

1675<chemistry id="CHEM-US-00430" num="00430"><img file="US8729293B2_D0430.tif" /></chemistry>

1676e is H or any one of the side chains of the naturally occurring amino acids;

1677W₃is null, —O—, or —N(R)—;

1678R is H or C₁-C₃alkyl; and

1679T is H, C(O)CH₃, or Z.

1680In some embodiments, W₁is O. In some embodiments, W₂is O.

1681In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

1682In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

1683In some embodiments, ----- represents a bond. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1684<chemistry id="CHEM-US-00431" num="00431"><img file="US8729293B2_D0431.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1685<chemistry id="CHEM-US-00432" num="00432"><img file="US8729293B2_D0432.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1686<chemistry id="CHEM-US-00433" num="00433"><img file="US8729293B2_D0433.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1687<chemistry id="CHEM-US-00434" num="00434"><img file="US8729293B2_D0434.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1688<chemistry id="CHEM-US-00435" num="00435"><img file="US8729293B2_D0435.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

1689<chemistry id="CHEM-US-00436" num="00436"><img file="US8729293B2_D0436.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1690<chemistry id="CHEM-US-00437" num="00437"><img file="US8729293B2_D0437.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1691<chemistry id="CHEM-US-00438" num="00438"><img file="US8729293B2_D0438.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1692<chemistry id="CHEM-US-00439" num="00439"><img file="US8729293B2_D0439.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1. In some embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

1693<chemistry id="CHEM-US-00440" num="00440"><img file="US8729293B2_D0440.tif" /></chemistry>

1694In some embodiments, Q is

1695<chemistry id="CHEM-US-00441" num="00441"><img file="US8729293B2_D0441.tif" /></chemistry>

1696In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In some embodiments, T is Z. In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H.

1697In yet another aspect, compounds of the Formula IIIa′ are described:

1698<chemistry id="CHEM-US-00442" num="00442"><img file="US8729293B2_D0442.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1699wherein

1700each W₁and W₂are independently null, O, or NH, or when W₁and W₂are both NH, then both W₁and W₂can be taken together to form a piperidine moiety;

1701----- represents an optional bond that when present requires that Q is null;

1702each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1703each b is H, CH₃, C(O)OH, or O—Z;

1704each d is H or C(O)OH;

1705each n, o, p, and q is independently 0 or 1;

1706each Z is H,

1707<chemistry id="CHEM-US-00443" num="00443"><img file="US8729293B2_D0443.tif" /></chemistry>

1708with the proviso that there is at least one

1709<chemistry id="CHEM-US-00444" num="00444"><img file="US8729293B2_D0444.tif" /></chemistry>

1710in the compound;

1711each r is independently 2, 3, or 7;

1712each s is independently 3, 5, or 6;

1713each t is independently 0 or 1;

1714each v is 1 or 2;

1715each R₅and R₆are independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

1716u is 0 or 1;

1717with the proviso that when r is 7, s is 3;

1718Q is null, C(O)CH₃, Z,

1719<chemistry id="CHEM-US-00445" num="00445"><img file="US8729293B2_D0445.tif" /></chemistry>

1720e is H or any one of the side chains of the naturally occurring amino acids;

1721W₃is null, —O—, or —N(R)—;

1722R is H or C₁-C₃alkyl; and

1723T is H, C(O)CH₃, or Z.

1724In some embodiments, W₁is O. In some embodiments, W₂is O. In some embodiments, ----- represents a bond. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1725<chemistry id="CHEM-US-00446" num="00446"><img file="US8729293B2_D0446.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1726<chemistry id="CHEM-US-00447" num="00447"><img file="US8729293B2_D0447.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1727<chemistry id="CHEM-US-00448" num="00448"><img file="US8729293B2_D0448.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1728<chemistry id="CHEM-US-00449" num="00449"><img file="US8729293B2_D0449.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1729<chemistry id="CHEM-US-00450" num="00450"><img file="US8729293B2_D0450.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

1730<chemistry id="CHEM-US-00451" num="00451"><img file="US8729293B2_D0451.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1731<chemistry id="CHEM-US-00452" num="00452"><img file="US8729293B2_D0452.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1732<chemistry id="CHEM-US-00453" num="00453"><img file="US8729293B2_D0453.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1733<chemistry id="CHEM-US-00454" num="00454"><img file="US8729293B2_D0454.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1. In some embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

1734<chemistry id="CHEM-US-00455" num="00455"><img file="US8729293B2_D0455.tif" /></chemistry>

1735In some embodiments, W₃is O. In other embodiments, W₃is N(R). In further embodiments, W₃is NH. In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H.

1736In some embodiments, Q is

1737<chemistry id="CHEM-US-00456" num="00456"><img file="US8729293B2_D0456.tif" /></chemistry>

1738In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In some embodiments, T is Z. In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H.

1739In another aspect, compounds of Formula IV′ are described herein:

1740<chemistry id="CHEM-US-00457" num="00457"><img file="US8729293B2_D0457.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1741wherein

1742W₁and W₂are each independently null, O, or NH;

1743----- represents an optional bond that when present requires that Q is null;

1744a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1745b is H, CH₃, C(O)OH, or O—Z;

1746d is H or C(O)OH;

1747each n, o, p, and q is independently 0 or 1;

1748each Z is H,

1749<chemistry id="CHEM-US-00458" num="00458"><img file="US8729293B2_D0458.tif" /></chemistry>

1750with the proviso that there is at least one

1751<chemistry id="CHEM-US-00459" num="00459"><img file="US8729293B2_D0459.tif" /></chemistry>

1752in the compound;

1753each r is independently 2 or 3;

1754each s is independently 5 or 6;

1755each t is independently 0 or 1;

1756each v is 1 or 2;

1757R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

1758Q is null, C(O)CH₃, Z, or

1759<chemistry id="CHEM-US-00460" num="00460"><img file="US8729293B2_D0460.tif" /></chemistry>

1760e is H, —C(O)OH, or any one of the side chains of the naturally occurring amino acids;

1761W₃is null, —O—, —N(R)—; and

1762R is H or C₁-C₃alkyl.

1763In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH.

1764In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

1765In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

1766In some embodiments, ----- represents a bond. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1767<chemistry id="CHEM-US-00461" num="00461"><img file="US8729293B2_D0461.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1768<chemistry id="CHEM-US-00462" num="00462"><img file="US8729293B2_D0462.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1769<chemistry id="CHEM-US-00463" num="00463"><img file="US8729293B2_D0463.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1770<chemistry id="CHEM-US-00464" num="00464"><img file="US8729293B2_D0464.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1771<chemistry id="CHEM-US-00465" num="00465"><img file="US8729293B2_D0465.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

1772<chemistry id="CHEM-US-00466" num="00466"><img file="US8729293B2_D0466.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1773<chemistry id="CHEM-US-00467" num="00467"><img file="US8729293B2_D0467.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1774<chemistry id="CHEM-US-00468" num="00468"><img file="US8729293B2_D0468.tif" /></chemistry><br /> and s is 5. In other embodiments 7 is

1775<chemistry id="CHEM-US-00469" num="00469"><img file="US8729293B2_D0469.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1. In some embodiments, Q is H. In other embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

1776<chemistry id="CHEM-US-00470" num="00470"><img file="US8729293B2_D0470.tif" /></chemistry>

1777In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H. In other embodiments, e is —C(O)OH. In some embodiments, W₃—NH—. In some embodiments, W₃is O.

1778In another aspect, compounds of the Formula IVa′ are described:

1779<chemistry id="CHEM-US-00471" num="00471"><img file="US8729293B2_D0471.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1780v is 1 or 2;

1781R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl; and

1782s is 5 or 6.

1783In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, s is 5. In some embodiments, s is 6.

1784In another aspect, compounds of the Formula IVb′ are described:

1785<chemistry id="CHEM-US-00472" num="00472"><img file="US8729293B2_D0472.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, enantiomers, and stereoisomers thereof, <br /> wherein

1786W₁and W₂are each independently null, O, or NH;

1787a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1788b is H, CH₃, C(O)OH, or O—Z;

1789d is H or C(O)OH;

1790each n, o, p, and q is independently 0 or 1;

1791each Z is H,

1792<chemistry id="CHEM-US-00473" num="00473"><img file="US8729293B2_D0473.tif" /></chemistry>

1793with the proviso that there is at least one

1794<chemistry id="CHEM-US-00474" num="00474"><img file="US8729293B2_D0474.tif" /></chemistry>

1795in the compound;

1796each r is independently 2 or 3;

1797each s is independently 5 or 6;

1798each t is independently 0 or 1;

1799each v is 1 or 2;

1800R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

1801In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

1802<chemistry id="CHEM-US-00475" num="00475"><img file="US8729293B2_D0475.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0.

1803In some embodiments, Z is

1804<chemistry id="CHEM-US-00476" num="00476"><img file="US8729293B2_D0476.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1805<chemistry id="CHEM-US-00477" num="00477"><img file="US8729293B2_D0477.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1806<chemistry id="CHEM-US-00478" num="00478"><img file="US8729293B2_D0478.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1807<chemistry id="CHEM-US-00479" num="00479"><img file="US8729293B2_D0479.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

1808<chemistry id="CHEM-US-00480" num="00480"><img file="US8729293B2_D0480.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1809<chemistry id="CHEM-US-00481" num="00481"><img file="US8729293B2_D0481.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1810<chemistry id="CHEM-US-00482" num="00482"><img file="US8729293B2_D0482.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1811<chemistry id="CHEM-US-00483" num="00483"><img file="US8729293B2_D0483.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is not H. In some embodiments, t is 1.

1812In another aspect, compounds of the Formula IVc′ are described:

1813<chemistry id="CHEM-US-00484" num="00484"><img file="US8729293B2_D0484.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1814W₁and W₂are each independently null, O, or NH;

1815a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1816b is H, CH₃, C(O)OH, or O—Z;

1817d is H or C(O)OH; each of n, o, p, and q is independently 0 or 1;

1818each Z is null, H,

1819<chemistry id="CHEM-US-00485" num="00485"><img file="US8729293B2_D0485.tif" /></chemistry>

1820with the proviso that there is at least one

1821<chemistry id="CHEM-US-00486" num="00486"><img file="US8729293B2_D0486.tif" /></chemistry>

1822in the compound;

1823each r is independently 2 or 3;

1824each s is independently 5 or 6;

1825each t is independently 0 or 1;

1826each v is 1 or 2;

1827R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

1828In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

1829<chemistry id="CHEM-US-00487" num="00487"><img file="US8729293B2_D0487.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1830<chemistry id="CHEM-US-00488" num="00488"><img file="US8729293B2_D0488.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1831<chemistry id="CHEM-US-00489" num="00489"><img file="US8729293B2_D0489.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1832<chemistry id="CHEM-US-00490" num="00490"><img file="US8729293B2_D0490.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1833<chemistry id="CHEM-US-00491" num="00491"><img file="US8729293B2_D0491.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

1834<chemistry id="CHEM-US-00492" num="00492"><img file="US8729293B2_D0492.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1835<chemistry id="CHEM-US-00493" num="00493"><img file="US8729293B2_D0493.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1836<chemistry id="CHEM-US-00494" num="00494"><img file="US8729293B2_D0494.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1837<chemistry id="CHEM-US-00495" num="00495"><img file="US8729293B2_D0495.tif" /></chemistry><br /> and s is 6. In some embodiments, at most one Z is H. In some embodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. In some embodiments, t is 1.

1838In another aspect, compounds of the Formula IVd′ are described:

1839<chemistry id="CHEM-US-00496" num="00496"><img file="US8729293B2_D0496.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1840each Z is null, H,

1841<chemistry id="CHEM-US-00497" num="00497"><img file="US8729293B2_D0497.tif" /></chemistry><br /> with the proviso that there is at least one

1842<chemistry id="CHEM-US-00498" num="00498"><img file="US8729293B2_D0498.tif" /></chemistry>

1843in the compound;

1844each r is independently 2 or 3;

1845each s is independently 5 or 6;

1846each t is independently 0 or 1;

1847each v is 1 or 2;

1848R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

1849In some embodiments, Z is

1850<chemistry id="CHEM-US-00499" num="00499"><img file="US8729293B2_D0499.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1851<chemistry id="CHEM-US-00500" num="00500"><img file="US8729293B2_D0500.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1852<chemistry id="CHEM-US-00501" num="00501"><img file="US8729293B2_D0501.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1853<chemistry id="CHEM-US-00502" num="00502"><img file="US8729293B2_D0502.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

1854<chemistry id="CHEM-US-00503" num="00503"><img file="US8729293B2_D0503.tif" /></chemistry><br /> and r is 2. In other embodiments; Z is

1855<chemistry id="CHEM-US-00504" num="00504"><img file="US8729293B2_D0504.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1856<chemistry id="CHEM-US-00505" num="00505"><img file="US8729293B2_D0505.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1857<chemistry id="CHEM-US-00506" num="00506"><img file="US8729293B2_D0506.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1.

1858In another aspect, compounds of the Formula IVe′ are described:

1859<chemistry id="CHEM-US-00507" num="00507"><img file="US8729293B2_D0507.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1860W₁is O, or NH;

1861W₂is null, O, or NH;

1862a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1863b is H, CH₃, C(O)OH, or O—Z;

1864d is H or C(O)OH;

1865each o, p, and q is independently 0 or 1;

1866each Z is H,

1867<chemistry id="CHEM-US-00508" num="00508"><img file="US8729293B2_D0508.tif" /></chemistry>

1868with the proviso that there is at least one

1869<chemistry id="CHEM-US-00509" num="00509"><img file="US8729293B2_D0509.tif" /></chemistry>

1870in the compound;

1871each r is independently 2 or 3;

1872each s is independently 5 or 6;

1873each t is independently 0 or 1;

1874each v is 1 or 2;

1875R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

1876In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1877<chemistry id="CHEM-US-00510" num="00510"><img file="US8729293B2_D0510.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1878<chemistry id="CHEM-US-00511" num="00511"><img file="US8729293B2_D0511.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1879<chemistry id="CHEM-US-00512" num="00512"><img file="US8729293B2_D0512.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1880<chemistry id="CHEM-US-00513" num="00513"><img file="US8729293B2_D0513.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1881<chemistry id="CHEM-US-00514" num="00514"><img file="US8729293B2_D0514.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

1882<chemistry id="CHEM-US-00515" num="00515"><img file="US8729293B2_D0515.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1883<chemistry id="CHEM-US-00516" num="00516"><img file="US8729293B2_D0516.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1884<chemistry id="CHEM-US-00517" num="00517"><img file="US8729293B2_D0517.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1885<chemistry id="CHEM-US-00518" num="00518"><img file="US8729293B2_D0518.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1.

1886In another aspect, compounds of the Formula IVf′ are described:

1887<chemistry id="CHEM-US-00519" num="00519"><img file="US8729293B2_D0519.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1888e is H, —C(O)OH or any one of the side chains of the naturally occurring amino acids;

1889W₃is null, —O—, —N(R)—; and

1890R is H or C₁-C₃alkyl,

1891v is 1 or 2;

1892s is 5 or 6; and

1893t is 0 or 1.

1894In some embodiments, W₃is O. In some embodiments, e is sec-butyl. In other embodiments, e is —C(O)OH. In still other embodiments, e is H. In some embodiments, W₃is —NR—. In some embodiments. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, s is 5. In some embodiments, s is 6. In some embodiments, v is 1. In other embodiments, v is 2. In some embodiments, t is 1.

1895In another aspect, compounds of the Formula IVg′ are described:

1896<chemistry id="CHEM-US-00520" num="00520"><img file="US8729293B2_D0520.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1897wherein

1898R is H or C₁-C₃alkyl;

1899W₁and W₂are each independently null, O, or NH;

1900a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1901b is H, CH₃, C(O)OH, or O—Z;

1902d is H or C(O)OH;

1903each n, o, p, and q is independently 0 or 1;

1904each Z is H,

1905<chemistry id="CHEM-US-00521" num="00521"><img file="US8729293B2_D0521.tif" /></chemistry>

1906with the proviso that there is at least one

1907<chemistry id="CHEM-US-00522" num="00522"><img file="US8729293B2_D0522.tif" /></chemistry>

1908in the compound;

1909each r is independently 2 or 3;

1910each s is independently 5 or 6;

1911each t is independently 0 or 1;

1912each v is 1 or 2;

1913R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

1914In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

1915<chemistry id="CHEM-US-00523" num="00523"><img file="US8729293B2_D0523.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1916<chemistry id="CHEM-US-00524" num="00524"><img file="US8729293B2_D0524.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1917<chemistry id="CHEM-US-00525" num="00525"><img file="US8729293B2_D0525.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1918<chemistry id="CHEM-US-00526" num="00526"><img file="US8729293B2_D0526.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1919<chemistry id="CHEM-US-00527" num="00527"><img file="US8729293B2_D0527.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

1920<chemistry id="CHEM-US-00528" num="00528"><img file="US8729293B2_D0528.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1921<chemistry id="CHEM-US-00529" num="00529"><img file="US8729293B2_D0529.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1922<chemistry id="CHEM-US-00530" num="00530"><img file="US8729293B2_D0530.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1923<chemistry id="CHEM-US-00531" num="00531"><img file="US8729293B2_D0531.tif" /></chemistry><br /> and s is 6. In some embodiments, at most one Z is H. In some embodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. In some embodiments, t is 1.

1924In still another aspect, compounds of the Formula V′ are described:

1925<chemistry id="CHEM-US-00532" num="00532"><img file="US8729293B2_D0532.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1926wherein

1927W₁and W₂are each independently null, O, or NH;

1928----- represents an optional bond that when present requires that Q is then null;

1929a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1930b is H, CH₃, C(O)OH, or O—Z;

1931d is H or C(O)OH;

1932each n, o, p, and q is independently 0 or 1;

1933each Z is independently null, H,

1934<chemistry id="CHEM-US-00533" num="00533"><img file="US8729293B2_D0533.tif" /></chemistry>

1935with the proviso that there is at least one

1936<chemistry id="CHEM-US-00534" num="00534"><img file="US8729293B2_D0534.tif" /></chemistry>

1937in the compound;

1938each r is independently 7;

1939each s is independently 3;

1940each t is independently 0 or 1;

1941each v is 1 or 2;

1942R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

1943Q is null, C(O)CH₃, Z, or

1944<chemistry id="CHEM-US-00535" num="00535"><img file="US8729293B2_D0535.tif" /></chemistry><br /> and

1945e is H, —C(O)OH or any one of the side chains of the naturally occurring amino acids.

1946In some embodiments, W₁is O. In some embodiments, W₁is NH. In some embodiments, W₂is O. In some embodiments, W₂is NH.

1947In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

1948In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

1949In some embodiments, ----- represents a bond. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1950<chemistry id="CHEM-US-00536" num="00536"><img file="US8729293B2_D0536.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

1951<chemistry id="CHEM-US-00537" num="00537"><img file="US8729293B2_D0537.tif" /></chemistry><br /> and r is 7. In some embodiments, Z is

1952<chemistry id="CHEM-US-00538" num="00538"><img file="US8729293B2_D0538.tif" /></chemistry><br /> and s is 3. In some embodiments, Z is

1953<chemistry id="CHEM-US-00539" num="00539"><img file="US8729293B2_D0539.tif" /></chemistry><br /> and r is 7. In other embodiments, Z is

1954<chemistry id="CHEM-US-00540" num="00540"><img file="US8729293B2_D0540.tif" /></chemistry><br /> and s is 3. In some embodiments, t is 1. In some embodiments, Q is C(O)CH₃, In some embodiments, Q is Z. In some embodiments, Q is

1955<chemistry id="CHEM-US-00541" num="00541"><img file="US8729293B2_D0541.tif" /></chemistry>

1956In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H. In other embodiments, e is —C(O)OH. In some embodiments, W₃—NR—. In some embodiments, W₃is O.

1957In yet another aspect, compounds of the Formula VI′ are described:

1958<chemistry id="CHEM-US-00542" num="00542"><img file="US8729293B2_D0542.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

1959wherein

1960W₁and W₂are each independently null, O, or NH;

1961----- represents an optional bond that when present requires that Q is null;

1962a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

1963b is H, CH₃, C(O)OH, or O—Z;

1964d is H or C(O)OH;

1965each n, o, p, and q is independently 0 or 1;

1966each Z is H,

1967<chemistry id="CHEM-US-00543" num="00543"><img file="US8729293B2_D0543.tif" /></chemistry>

1968with the proviso that there is at least one

1969<chemistry id="CHEM-US-00544" num="00544"><img file="US8729293B2_D0544.tif" /></chemistry>

1970in the compound;

1971each r is independently 0, 1, 2, or 3;

1972each s is independently an integer from 1 to 10;

1973each t is independently 0 or 1;

1974each v is 1 or 2;

1975R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

1976Q is null, C(O)CH₃, Z, or

1977<chemistry id="CHEM-US-00545" num="00545"><img file="US8729293B2_D0545.tif" /></chemistry>

1978e is H, —C(O)OH, or any one of the side chains of the naturally occurring amino acids;

1979W₃is null, —O—, —N(R)—; and

1980R is H or C₁-C₃alkyl.

1981In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH.

1982In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

1983In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

1984In some embodiments, ----- represents a bond. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

1985<chemistry id="CHEM-US-00546" num="00546"><img file="US8729293B2_D0546.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1.

1986In some embodiments, n is 0. In some embodiments, Z is

1987<chemistry id="CHEM-US-00547" num="00547"><img file="US8729293B2_D0547.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

1988<chemistry id="CHEM-US-00548" num="00548"><img file="US8729293B2_D0548.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1989<chemistry id="CHEM-US-00549" num="00549"><img file="US8729293B2_D0549.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

1990<chemistry id="CHEM-US-00550" num="00550"><img file="US8729293B2_D0550.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

1991<chemistry id="CHEM-US-00551" num="00551"><img file="US8729293B2_D0551.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

1992<chemistry id="CHEM-US-00552" num="00552"><img file="US8729293B2_D0552.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

1993<chemistry id="CHEM-US-00553" num="00553"><img file="US8729293B2_D0553.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

1994<chemistry id="CHEM-US-00554" num="00554"><img file="US8729293B2_D0554.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1. In some embodiments, Q is H. In other embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

1995<chemistry id="CHEM-US-00555" num="00555"><img file="US8729293B2_D0555.tif" /></chemistry>

1996In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H. In other embodiments, e is —C(O)OH. In some embodiments, W₃is —NR—. In some embodiments, W₃is O.

1997In another aspect, compounds of the Formula VIa′ are described:

1998<chemistry id="CHEM-US-00556" num="00556"><img file="US8729293B2_D0556.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

1999v is 1 or 2;

2000R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl; and

2001s is independently 5 or 6.

2002In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, s is 5. In some embodiments, s is 6.

2003In another aspect, compounds of the Formula VIb′ are described:

2004<chemistry id="CHEM-US-00557" num="00557"><img file="US8729293B2_D0557.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, enantiomers, and stereoisomers thereof, <br /> wherein

2005W₁and W₂are each independently null, O, or NH;

2006a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

2007b is H, CH₃, C(O)OH, or O—Z;

2008d is H or C(O)OH;

2009each n, o, p, and q is independently 0 or 1;

2010each Z is H,

2011<chemistry id="CHEM-US-00558" num="00558"><img file="US8729293B2_D0558.tif" /></chemistry>

2012with the proviso that there is at least one

2013<chemistry id="CHEM-US-00559" num="00559"><img file="US8729293B2_D0559.tif" /></chemistry>

2014in the compound;

2015each r is independently 2 or 3;

2016each s is independently 5 or 6;

2017each t is independently 0 or 1;

2018each v is 1 or 2;

2019R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

2020In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

2021<chemistry id="CHEM-US-00560" num="00560"><img file="US8729293B2_D0560.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0.

2022In some embodiments, Z is

2023<chemistry id="CHEM-US-00561" num="00561"><img file="US8729293B2_D0561.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

2024<chemistry id="CHEM-US-00562" num="00562"><img file="US8729293B2_D0562.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

2025<chemistry id="CHEM-US-00563" num="00563"><img file="US8729293B2_D0563.tif" /></chemistry><br /> and s is 5. In some embodiments. Z is

2026<chemistry id="CHEM-US-00564" num="00564"><img file="US8729293B2_D0564.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

2027<chemistry id="CHEM-US-00565" num="00565"><img file="US8729293B2_D0565.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

2028<chemistry id="CHEM-US-00566" num="00566"><img file="US8729293B2_D0566.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

2029<chemistry id="CHEM-US-00567" num="00567"><img file="US8729293B2_D0567.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

2030<chemistry id="CHEM-US-00568" num="00568"><img file="US8729293B2_D0568.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is not H. In some embodiments, t is 1.

2031In another aspect, compounds of the Formula VIc′ are described:

2032<chemistry id="CHEM-US-00569" num="00569"><img file="US8729293B2_D0569.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

2033W₁and W₂are each independently null, O, or NH;

2034a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

2035b is H, CH₃, C(O)OH, or O—Z;

2036d is H or C(O)OH; each of n, o, p, and q is independently 0 or 1;

2037each Z is independently null, H,

2038<chemistry id="CHEM-US-00570" num="00570"><img file="US8729293B2_D0570.tif" /></chemistry>

2039with the proviso that there is at least one

2040<chemistry id="CHEM-US-00571" num="00571"><img file="US8729293B2_D0571.tif" /></chemistry>

2041in the compound;

2042each r is independently 2 or 3;

2043each s is independently 5 or 6;

2044each t is independently 0 or 1;

2045each v is 1 or 2;

2046R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

2047In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

2048<chemistry id="CHEM-US-00572" num="00572"><img file="US8729293B2_D0572.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1.

2049In some embodiments, n is 0. In some embodiments, Z is

2050<chemistry id="CHEM-US-00573" num="00573"><img file="US8729293B2_D0573.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

2051<chemistry id="CHEM-US-00574" num="00574"><img file="US8729293B2_D0574.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

2052<chemistry id="CHEM-US-00575" num="00575"><img file="US8729293B2_D0575.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

2053<chemistry id="CHEM-US-00576" num="00576"><img file="US8729293B2_D0576.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

2054<chemistry id="CHEM-US-00577" num="00577"><img file="US8729293B2_D0577.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

2055<chemistry id="CHEM-US-00578" num="00578"><img file="US8729293B2_D0578.tif" /></chemistry><br /> and r is 3. In some embodiments 7 is

2056<chemistry id="CHEM-US-00579" num="00579"><img file="US8729293B2_D0579.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

2057<chemistry id="CHEM-US-00580" num="00580"><img file="US8729293B2_D0580.tif" /></chemistry><br /> and s is 6. In some embodiments, at most one Z is H. In some embodiments, Z is not H.

2058In other embodiments, Z is not —C(O)CH₃. In some embodiments, t is 1.

2059In another aspect, compounds of the Formula VId′ are described:

2060<chemistry id="CHEM-US-00581" num="00581"><img file="US8729293B2_D0581.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

2061each Z is independently H,

2062<chemistry id="CHEM-US-00582" num="00582"><img file="US8729293B2_D0582.tif" /></chemistry>

2063with the proviso that there is at least one

2064<chemistry id="CHEM-US-00583" num="00583"><img file="US8729293B2_D0583.tif" /></chemistry>

2065in the compound;

2066each r is independently 2 or 3;

2067each s is independently 5 or 6;

2068each t is independently 0 or 1;

2069each v is 1 or 2;

2070R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

2071In some embodiments, Z is

2072<chemistry id="CHEM-US-00584" num="00584"><img file="US8729293B2_D0584.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

2073<chemistry id="CHEM-US-00585" num="00585"><img file="US8729293B2_D0585.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

2074<chemistry id="CHEM-US-00586" num="00586"><img file="US8729293B2_D0586.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

2075<chemistry id="CHEM-US-00587" num="00587"><img file="US8729293B2_D0587.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

2076<chemistry id="CHEM-US-00588" num="00588"><img file="US8729293B2_D0588.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

2077<chemistry id="CHEM-US-00589" num="00589"><img file="US8729293B2_D0589.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

2078<chemistry id="CHEM-US-00590" num="00590"><img file="US8729293B2_D0590.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

2079<chemistry id="CHEM-US-00591" num="00591"><img file="US8729293B2_D0591.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1.

2080In another aspect, compounds of the Formula VIe′ are described:

2081<chemistry id="CHEM-US-00592" num="00592"><img file="US8729293B2_D0592.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

2082W₁is O, or NH;

2083W₂is null, O, or NH;

2084a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

2085b is H, CH₃, C(O)OH, or O—Z;

2086d is H or C(O)OH;

2087each o, p, and q is independently 0 or 1;

2088each Z is H,

2089<chemistry id="CHEM-US-00593" num="00593"><img file="US8729293B2_D0593.tif" /></chemistry>

2090with the proviso that there is at least one

2091<chemistry id="CHEM-US-00594" num="00594"><img file="US8729293B2_D0594.tif" /></chemistry>

2092in the compound;

2093each r is independently 2 or 3;

2094each s is

2095independently 5 or 6;

2096each t is independently 0 or 1;

2097each v is 1 or 2;

2098R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

2099In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

2100<chemistry id="CHEM-US-00595" num="00595"><img file="US8729293B2_D0595.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1. In some embodiments, n is 0. In some embodiments, Z is

2101<chemistry id="CHEM-US-00596" num="00596"><img file="US8729293B2_D0596.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

2102<chemistry id="CHEM-US-00597" num="00597"><img file="US8729293B2_D0597.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

2103<chemistry id="CHEM-US-00598" num="00598"><img file="US8729293B2_D0598.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

2104<chemistry id="CHEM-US-00599" num="00599"><img file="US8729293B2_D0599.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

2105<chemistry id="CHEM-US-00600" num="00600"><img file="US8729293B2_D0600.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

2106<chemistry id="CHEM-US-00601" num="00601"><img file="US8729293B2_D0601.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

2107<chemistry id="CHEM-US-00602" num="00602"><img file="US8729293B2_D0602.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

2108<chemistry id="CHEM-US-00603" num="00603"><img file="US8729293B2_D0603.tif" /></chemistry><br /> and s is 6. In some embodiments, t is 1.

2109In another aspect, compounds of the Formula VIP are described:

2110<chemistry id="CHEM-US-00604" num="00604"><img file="US8729293B2_D0604.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; <br /> wherein

2111e is H, —C(O)OH or any one of the side chains of the naturally occurring amino acids;

2112W₃is null, —O—, —N(R)—; and

2113R is H or C₁-C₃alkyl,

2114each v is 1 or 2;

2115each R₅and R₆are independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl; and

2116s is 5 or 6.

2117In some embodiments, W₃is O. In some embodiments, e is sec-butyl. In other embodiments, e is —C(O)OH. In still other embodiments, e is H. In some embodiments, W₃is —NR—. In some embodiments, W₃is O. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, s is 5. In some embodiments, s is 6. In some embodiments, t is 1.

2118In another aspect, compounds of the Formula VIg′ are described:

2119<chemistry id="CHEM-US-00605" num="00605"><img file="US8729293B2_D0605.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

2120wherein

2121R is H or C₁-C₃alkyl;

2122W₁and W₂are each independently null, O, or NH;

2123a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

2124b is H, CH₃, C(O)OH, or O—Z;

2125d is H or C(O)OH;

2126each n, o, p, and q is independently 0 or 1;

2127each Z is H,

2128<chemistry id="CHEM-US-00606" num="00606"><img file="US8729293B2_D0606.tif" /></chemistry>

2129with the proviso that there is at least one

2130<chemistry id="CHEM-US-00607" num="00607"><img file="US8729293B2_D0607.tif" /></chemistry>

2131in the compound;

2132each r is independently 2 or 3;

2133each s is independently 5 or 6;

2134each t is independently 0 or 1;

2135each v is 1 or 2;

2136R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl.

2137In some embodiments, W₁is O. In other embodiments, W₁is NH. In some embodiments, W₂is O. In other embodiments, W₂is NH. In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH; In some embodiments, b is O—Z, Z is

2138<chemistry id="CHEM-US-00608" num="00608"><img file="US8729293B2_D0608.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1.

2139In some embodiments, n is 0. In some embodiments, Z is

2140<chemistry id="CHEM-US-00609" num="00609"><img file="US8729293B2_D0609.tif" /></chemistry><br /> and r is 2. In some embodiments, Z is

2141<chemistry id="CHEM-US-00610" num="00610"><img file="US8729293B2_D0610.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

2142<chemistry id="CHEM-US-00611" num="00611"><img file="US8729293B2_D0611.tif" /></chemistry><br /> and s is 5. In some embodiments, Z is

2143<chemistry id="CHEM-US-00612" num="00612"><img file="US8729293B2_D0612.tif" /></chemistry><br /> and s is 6. In some embodiments, Z is

2144<chemistry id="CHEM-US-00613" num="00613"><img file="US8729293B2_D0613.tif" /></chemistry><br /> and r is 2. In other embodiments, Z is

2145<chemistry id="CHEM-US-00614" num="00614"><img file="US8729293B2_D0614.tif" /></chemistry><br /> and r is 3. In some embodiments, Z is

2146<chemistry id="CHEM-US-00615" num="00615"><img file="US8729293B2_D0615.tif" /></chemistry><br /> and s is 5. In other embodiments, Z is

2147<chemistry id="CHEM-US-00616" num="00616"><img file="US8729293B2_D0616.tif" /></chemistry><br /> and s is 6. In some embodiments, at most one Z is H. In some embodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. In some embodiments, t is 1.

2148In another aspect, compounds of the Formula VII′ are described:

2149<chemistry id="CHEM-US-00617" num="00617"><img file="US8729293B2_D0617.tif" /></chemistry><br /> and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

2150wherein

2151W₁and W₂are each independently null, O, or NH;

2152----- represents an optional bond that when present requires that Q is then null;

2153a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

2154b is H, CH₃, C(O)OH, or O—Z;

2155d is H or C(O)OH;

2156each n, o, p, and q is independently 0 or 1;

2157each Z is H,

2158<chemistry id="CHEM-US-00618" num="00618"><img file="US8729293B2_D0618.tif" /></chemistry>

2159with the proviso that there is at least one

2160<chemistry id="CHEM-US-00619" num="00619"><img file="US8729293B2_D0619.tif" /></chemistry>

2161in the compound;

2162each r is independently 7;

2163each s is independently 3;

2164each t is independently 0 or 1;

2165each v is 1 or 2;

2166R₅and R₆are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃alkene, —C₁-C₃alkyne, —C(O)C₁-C₄alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃alkyl)₂, —NH(C(O)C₁-C₃alkyl), —N(C(O)C₁-C₃alkyl)₂, —SH, —S(C₁-C₃alkyl), —S(O)C₁-C₃alkyl, —S(O)₂C₁-C₃alkyl;

2167Q is null, C(O)CH₃, Z, or

2168<chemistry id="CHEM-US-00620" num="00620"><img file="US8729293B2_D0620.tif" /></chemistry>

2169W₃is null, —O—, —N(R)—;

2170R is H or C₁-C₃alkyl; and

2171e is H, —C(O)OH or any one of the side chains of the naturally occurring amino acids.

2172In some embodiments, W₁is O. In some embodiments, W₁is NH. In some embodiments, W₂is O. In some embodiments, W₂is NH.

2173In some embodiments, W₁is N. In other embodiments W₁is N substituted with a C₁-C₆alkyl. In other embodiments, W₁is an oxidized N.

2174In some embodiments, W₂is N. In other embodiments W₂is N substituted with a C₁-C₆alkyl. In other embodiments, W₂is an oxidized N.

2175In some embodiments, ----- represents a bond. In some embodiments, a and c are each, independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In some embodiments, b is O—Z, Z is

2176<chemistry id="CHEM-US-00621" num="00621"><img file="US8729293B2_D0621.tif" /></chemistry><br /> and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o, p, and q are each 1.

2177In some embodiments, n is 0. In some embodiments, Z is

2178<chemistry id="CHEM-US-00622" num="00622"><img file="US8729293B2_D0622.tif" /></chemistry><br /> and r is 7. In some embodiments, Z is

2179<chemistry id="CHEM-US-00623" num="00623"><img file="US8729293B2_D0623.tif" /></chemistry><br /> and s is 3. In some embodiments, Z is

2180<chemistry id="CHEM-US-00624" num="00624"><img file="US8729293B2_D0624.tif" /></chemistry><br /> and r is 7. In other embodiments, Z is

2181<chemistry id="CHEM-US-00625" num="00625"><img file="US8729293B2_D0625.tif" /></chemistry><br /> and s is 3. In some embodiments, t is 1. In some embodiments, Q is C(O)CH₃, In some embodiments, Q is Z. In some embodiments, Q is

2182<chemistry id="CHEM-US-00626" num="00626"><img file="US8729293B2_D0626.tif" /></chemistry>

2183In some embodiments, e is any one of the side chains of the naturally occurring amino acids. In some embodiments, e is H. In other embodiments, e is —C(O)OH. In some embodiments, W₃is —NR—. In some embodiments, W₃is O.

2184In any of the above Formulae, any one or more of H may be substituted with a deuterium. It is also understood in any of the above Formulae that a methyl substituent can be substituted with a C₁-C₆alkyl.

0000Methods for using Compounds of the Invention

2185The invention also includes methods for upregulating an anti-inflammatory pathway and downregulating a proinflammatory pathway in a cell.

2186In one embodiment, the method comprises contacting a cell with a Compound of the Invention in an amount sufficient to upregulate an anti-inflammatory pathway and down regulate a proinflammatory pathway in the cell. In general, any cell having, or capable of having, inflammatory activity or capable of expressing NFκB can be used. The cell can be provided in any form. For example, the cell can be provided in vitro, ex vivo, or in vivo. Inflammatory activity can be measured using any method known in the art, e.g., methods as described in Tran P. O., et al., <i>Diabetes, </i>51; 1772-8, 2002. Illustrative examples of cells capable of inflammatory activity include, but are not limited to, immune cells including monocytes, macrophages, T-cell, Th-1, Th-2, Th-17, Treg, lymphocytes, spleen cells, muscle, adipose or fat, vascular cells such as endothelial or pericyte, bone, gum, nerve, brain, glial, astrocytes, nerve, liver, kidney, pancreas including islet cells such as beta cells, lung, heart, breast, bladder, stomach, colon, rectal, small intestine, skin, esophageal, eye, larynx, uterine, ovarian, prostate, tendon, bone marrow, blood, lymph, testicular, vaginal and neoplastic cells.

2187Also provided in the invention is a method for inhibiting, preventing, or treating inflammation or an inflammatory disease in a subject. The inflammation can be associated with an inflammatory disease or a disease where inflammation contributes to the disease. Inflammatory diseases can arise where there is an inflammation of the body tissue. These include local inflammatory responses and systemic inflammation. Examples of such diseases include, but are not limited to: organ transplant rejection; reoxygenation injury resulting from organ transplantation (see Grupp et al., J. Mol. Cell. Cardiol. 31: 297-303 (1999)) including, but not limited to, transplantation of the following organs: heart, lung, liver and kidney; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases such as asthma, adult respiratory distress syndrome, chronic obstructive airway disease, and cystic fibrosis; inflammatory diseases of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; inflammatory diseases of the kidney including uremic complications, glomerulonephritis and nephrosis; inflammatory diseases of the skin including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis. Metabolic disease such as type II diabetes mellitus; the prevention of type I diabetes; dyslipedemia; hypertriglyceridemia; diabetic complications, including, but not limited to glaucoma, retinopathy, macula edema, nephropathy, such as microalbuminuria and progressive diabetic nephropathy, polyneuropathy, diabetic neuropathy, atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemichyperosmolar coma, mononeuropathies, autonomic neuropathy, joint problems, and a skin or mucous membrane complication, such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorum; immune-complex vasculitis, systemic lupus erythematosus; inflammatory diseases of the heart such as cardiomyopathy, ischemic heart disease hypercholesterolemia, and atherosclerosis; as well as various other diseases that can have significant inflammatory components, including preeclampsia; chronic liver failure, brain and spinal cord trauma, and cancer. The inflammatory disease can also be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to proinflammatory cytokines, e.g., shock associated with proinflammatory cytokines. Such shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer. Other disorders include depression, obesity, allergic diseases, acute cardiovascular events, arrhythmia, prevention of sudden death, muscle wasting diseases such as Duchenne's Muscular Dystrophy, inflammatory myopathies such as dermatomositis, inclusion body myositis, and polymyositis, and cancer cachexia. Also inflammation that results from surgery and trauma can be treated with Compound of the Invention.

2188In some embodiments, the subject is administered an effective amount of a Compound of the Invention.

2189The invention also includes pharmaceutical compositions useful for treating or preventing an inflammatory disease, or for inhibiting inflammation activity, or more than one of these activities. The compositions can be suitable for internal use and comprise an effective amount of a Compound of the Invention and a pharmaceutically acceptable carrier. The Compounds of the Invention are especially useful in that they demonstrate very low peripheral toxicity or no peripheral toxicity.

2190The Compounds of the Invention can each be administered in amounts that are sufficient to treat or prevent an inflammatory disease or a reperfusion disease and/or prevent the development thereof in subjects.

2191Administration of the Compounds of the Invention can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.

2192Depending on the intended mode of administration, the compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those skilled in the pharmaceutical arts.

2193Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a Compound of the Invention and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algiic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

2194Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the Compound of the Invention is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the Compounds of the Invention.

2195The Compounds of the Invention can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

2196The Compounds of the Invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564.

2197Compounds of the Invention can also be delivered by the use of monoclonal antibodies as individual carriers to which the Compounds of the Invention are coupled. The Compounds of the Invention can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the Compounds of the Invention can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, Compounds of the Invention are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.

2198Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

2199Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the Compound of the Invention by weight or volume.

2200The dosage regimen utilizing the Compound of the Invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular Compound of the Invention employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

2201Effective dosage amounts of the present invention, when used for the indicated effects, range from about 20 mg to about 5000 mg of the Compound of the Invention per day. Compositions for in vivo or in vitro use can contain about 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the Compound of the Invention. In one embodiment, the compositions are in the form of a tablet that can be scored. Effective plasma levels of the Compound of the Invention can range from about 0.002 mg to about 100 mg per kg of body weight per day. Appropriate dosages of the Compounds of the Invention can be determined as set forth in L. S. Goodman, et al., <i>The Pharmacological Basis of Therapeutics, </i>201-26 (5th ed. 1975).

2202Compounds of the Invention can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, Compounds of the Invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen. Other illustrative topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of the Compound of the Invention ranges from about 0.1% to about 15%, w/w or w/v.

0000Methods for Making the Fatty Acid Acetylated Salicylate Derivatives

2203Examples of synthetic pathways useful for making Fatty Acid Acetylated Salicylate Derivatives of Formula I, Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, and Formula II are set forth in the Examples below and generalized in Schemes 1-4.

2204<chemistry id="CHEM-US-00627" num="00627"><img file="US8729293B2_D0627.tif" /></chemistry>

2205wherein r and s are as defined above for Formula I, Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, and Formula II.

2206Compound A can be esterified in the presence of acid catalyst and a suitable alcohol, e.g., ethanol to give ester B. Activation of compound B with a coupling reagent such as for example DCC, CDI, or EDC, optionally with a tertiary amine base and/or catalyst, e.g., DMAP, followed by addition of a fatty acid of Formula C affords compounds of Formula D. Alternatively, compound A can be esterified with benzyl bromide in the presence of base, e.g., CsCO₃, then subjected to the remaining steps of Scheme 1. Hydrogenolysis of the benzyl ester derived from A, for example using Pd/C and H2, can yield the free acid of compounds of Formula D.

2207<chemistry id="CHEM-US-00628" num="00628"><img file="US8729293B2_D0628.tif" /></chemistry>

2208wherein r and s are as defined above for compounds of Formula I, Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, Formula II, and Formula III.

2209Compound A can be esterified in the presence of acid catalyst and a suitable protecting alcohol such as, e.g., t-butanol, followed by coupling to an activated amino acid to give compound F. Condensation of the amino compound F with a fatty acid chloride of Formula G affords compounds of Formula H. The ester may be deprotected using methods disclosed in Greene, et al. <i>Protecting Groups in Organic Chemistry. </i>4^thed. Wiley &amp; Sons, Hoboken, N.J. (2007). See, e.g., Chapter 5, therein.

2210<chemistry id="CHEM-US-00629" num="00629"><img file="US8729293B2_D0629.tif" /></chemistry>

2211wherein r and s are as defined above for Formula I, Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, and Formula II.

2212Acid I can be activated by esterification with a suitable activating agent such as, e.g., pivoyl chloride, followed by condensation with an amino alcohol such as for example n-propanolamine, to give compound K. Condensation of the alcohol compound K with a fatty acid chloride of Formula G affords compounds of Formula L. Diacylated compounds of the invention can be made by subjecting compound A to the above procedure.

2213<chemistry id="CHEM-US-00630" num="00630"><img file="US8729293B2_D0630.tif" /></chemistry>

2214wherein r and s are as defined above for Formula I, Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, and Formula II.

2215Activated ester J (see Scheme 3) can be condensed with an amino-masked diol M, which after acid workup gives the unmasked diol compound N. Condensation of the diol compound N with a fatty acid chloride of Formula G affords compounds of Formula O.

0000Methods for Making the Fatty Acid Acetylated Diflunisal Derivatives

2216Examples of synthetic pathways useful for making Fatty Acid Acetylated Diflunisal Derivatives of Formula IV, Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, Formula IVf, Formula IVg, and Formula V, are set forth herein and generalized in Schemes 5-9.

2217<chemistry id="CHEM-US-00631" num="00631"><img file="US8729293B2_D0631.tif" /></chemistry><br /> wherein r and s are as defined for Formula IV, Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, Formula IVf, Formula IVg, and Formula V.

2218Compound P can be esterified in the presence of acid catalyst and a suitable alcohol, e.g., ethanol to give ester Q. Activation of compound Q with a coupling reagent such as for example DCC, CDI, or EDC, optionally with a tertiary amine base and/or catalyst, e.g., DMAP, followed by addition of a fatty acid of Formula C affords compounds of Formula R. Alternatively, compound P can be esterified with benzyl bromide in the presence of base, e.g., CsCO₃, then subjected to the remaining steps of Scheme 5. Hydrogenolysis of the benzyl ester derived from P, for example using Pd/C and H2, can yield the free acid of compounds of Formula R.

2219<chemistry id="CHEM-US-00632" num="00632"><img file="US8729293B2_D0632.tif" /></chemistry><br /> wherein r and s are as defined for Formula IV, Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, Formula IVf, Formula IVg, and Formula V.

2220Compound P can be esterified in the presence of acid catalyst and a suitable protecting alcohol such as, e.g., t-butanol, followed by coupling to an activated amino acid to give compound S. Condensation of the amino compound S with a fatty acid chloride of Formula G affords compounds of Formula T. The ester may be deprotected using methods disclosed in Greene, et al. <i>Protecting Groups in Organic Chemistry. </i>4^thed. Wiley &amp; Sons, Hoboken, N.J. (2007). See, e.g., Chapter 5, therein.

2221<chemistry id="CHEM-US-00633" num="00633"><img file="US8729293B2_D0633.tif" /></chemistry><br /> wherein r and s are as defined above for Formula IV, Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, Formula IVf, Formula IVg, and Formula V.

2222Acid U can be activated by esterification with a suitable activating agent such as, e.g., pivoyl chloride, followed by condensation with an amino alcohol such as for example n-propanolamine, to give compound W. Condensation of the alcohol compound W with a fatty acid chloride of Formula G affords compounds of Formula X. Diacylated compounds of the invention can be made by subjecting compound P to the above procedure.

2223<chemistry id="CHEM-US-00634" num="00634"><img file="US8729293B2_D0634.tif" /></chemistry><br /> wherein r and s are as defined above for Formula IV, Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, Formula IVf, Formula IVg, and Formula V.

2224Activated ester V (see Scheme 7) can be condensed with a amino-masked diol M, which after acid workup gives the unmasked diol compound Z. Condensation of the diol compound Z with a fatty acid chloride of Formula G affords compounds of Formula AA.

2225<chemistry id="CHEM-US-00635" num="00635"><img file="US8729293B2_D0635.tif" /></chemistry><br /> wherein r and s are as defined for Formula IV, Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, Formula IVf, Formula IVg, and Formula V.

2226Compound P can be esterified with benzyl bromide in the presence of a base, e.g. CsCO₃yielding compound BB. Condensation of compound BB with a fatty acid chloride of Formula G affords compounds of Formula CC. Hydrogenolysis of the benzyl ester of compounds of Formula CC, e.g. using Pd/C and H₂, yields compounds of Formula DD.

0000Methods for Making the Fatty Acid Acetylated Triflusal Derivatives

2227Examples of synthetic pathways useful for making Fatty Acid Acetylated Triflusal Derivatives of Formula VI, Formula VIa, Formula VIb, Formula VIc, Formula VId, Formula VIe, Formula VIf, Formula VIg, and Formula VII, are set forth herein and generalized in Schemes 10-14.

2228<chemistry id="CHEM-US-00636" num="00636"><img file="US8729293B2_D0636.tif" /></chemistry><br /> wherein r and s are as defined above for Formula VI, Formula VIa, Formula VIb, Formula VIc, Formula VId, Formula VIe, Formula VIf, Formula VIg, and Formula VII.

2229Compound EE can be esterified in the presence of acid catalyst and a suitable alcohol, e.g., ethanol to give ester FF. Activation of compound FF with a coupling reagent such as for example DCC, CDI, or EDC, optionally with a tertiary amine base and/or catalyst, e.g., DMAP, followed by addition of a fatty acid of Formula C affords compounds of Formula GG.

2230Alternatively, compound EE can be esterified with benzyl bromide in the presence of base, e.g., CsCO₃, then subjected to the remaining steps of Scheme 1. Hydrogenolysis of the benzyl ester derived from EE, for example using Pd/C and H₂, can yield the free acid of compounds of Formula GG.

2231<chemistry id="CHEM-US-00637" num="00637"><img file="US8729293B2_D0637.tif" /></chemistry><br /> wherein r, s and u can be as described for Formula VI, Formula VIa, Formula VIb, Formula VIc, Formula VId, Formula VIe, Formula VIf, Formula VIg, and Formula VII.

2232Compound EE can be esterified in the presence of acid catalyst and a suitable protecting alcohol such as, e.g., t-butanol, followed by coupling to an activated amino acid to give compound HH. Condensation of the amino compound HH with a fatty acid chloride of Formula G affords compounds of Formula JJ. The ester may be deprotected using methods disclosed in Greene, et al. <i>Protecting Groups in Organic Chemistry. </i>4^thed. Wiley &amp; Sons, Hoboken, N.J. (2007). See, e.g., Chapter 5, therein.

2233<chemistry id="CHEM-US-00638" num="00638"><img file="US8729293B2_D0638.tif" /></chemistry><br /> wherein r and s are as defined above for Formula VI, Formula VIa, Formula VIb, Formula VIe, Formula VId, Formula VIe, Formula VIf, Formula VIg, and Formula VII.

2234Acid KK can be activated by esterification with a suitable activating agent such as, e.g., pivoyl chloride, followed by condensation with an amino alcohol such as for example n-propanolamine, to give compound MM. Condensation of the alcohol compound MM with a fatty acid chloride of Formula G affords compounds of Formula NN. Diacylated compounds of the invention can be made by subjecting compound EE to the above procedure.

2235<chemistry id="CHEM-US-00639" num="00639"><img file="US8729293B2_D0639.tif" /></chemistry><br /> wherein r and s are as defined above for Formula VI, Formula VIa, Formula VIb, Formula VIc, Formula VId, Formula VIe, Formula VIf, Formula VIg, and Formula VII.

2236Activated ester LL (see Scheme 12) can be condensed with a amino-masked diol M, which after acid workup gives the unmasked diol compound OO. Condensation of the diol compound OO with a fatty acid chloride of Formula G affords compounds of Formula PP.

2237<chemistry id="CHEM-US-00640" num="00640"><img file="US8729293B2_D0640.tif" /></chemistry><br /> wherein r and s are as defined above for Formula VI, Formula VIa, Formula VIb, Formula VIc, Formula VId, Formula VIe, Formula VIf, Formula VIg, and Formula VII.

2238Compound EE can be esterified with benzyl bromide in the presence of a base, e.g. CsCO₃yielding compound QQ. Condensation of compound QQ with a fatty acid chloride of Formula G affords compounds of Formula RR. Hydrogenolysis of the benzyl ester of compounds of Formula RR, e.g. using Pd/C and H₂, yields compounds of Formula SS.

0000Methods for Making the Fatty Acid Acetylated Amino Salicylate Derivatives

2239Examples of synthetic pathways useful for making Fatty Acid Acetylated Amino Salicylate Derivatives of Formula III are set forth in the Examples below and generalized in Schemes 15-18.

2240<chemistry id="CHEM-US-00641" num="00641"><img file="US8729293B2_D0641.tif" /></chemistry><br /> wherein r and s are as defined for Formula III.

2241Compound TT can be esterified in the presence of acid catalyst and a suitable alcohol, e.g., methanol to give ester UU. Activation of compound UU with a coupling reagent such as for example DCC, CDI, or EDC, optionally with a tertiary amine base and/or catalyst, e.g., DMAP, followed by addition of a fatty acid of Formula C affords compounds of Formula VV. Saponification of the esters of Formula VV with a suitable base, such as for example NaOH, can yield the free acid of compounds of Formula VV. Alternatively, compound TT can be esterified with benzyl bromide in the presence of base, e.g., CsCO₃, then subjected to the remaining steps of Scheme 1. Hydrogenolysis of the benzyl ester derived from TT, for example using Pd/C and H₂, can yield the free acid of compounds of Formula VV. Diacylated compounds of the invention can be made by subjecting compound TT to the above procedure.

2242<chemistry id="CHEM-US-00642" num="00642"><img file="US8729293B2_D0642.tif" /></chemistry><br /> wherein r and s are as defined for Formula III.

2243Isocyanide WW can be condensed with an amino-masked ethanolamine XX, which after acid workup gives the unmasked aminocarbamate compound YY. Activation of compound YY with a coupling reagent such as for example DCC, CDI, or EDC, optionally with a tertiary amine base and/or catalyst, e.g., DMAP, followed by addition of a fatty acid of Formula C affords compounds of Formula ZZ. The ester may be deprotected using methods disclosed in Greene, et al. Protecting Groups in Organic Chemistry. 4^thed. Wiley &amp; Sons, Hoboken, N.J. (2007). See, e.g., Chapter 5, therein.

2244<chemistry id="CHEM-US-00643" num="00643"><img file="US8729293B2_D0643.tif" /></chemistry><br /> wherein r and s are as defined for Formula III.

2245Isocyanide WW can be condensed with an mono amino-masked ethylenediamine AAA, which after acid workup gives the unmasked urea compound BBB. Activation of compound BBB with a coupling reagent such as for example DCC, CDI, or EDC, optionally with a tertiary amine base and/or catalyst, e.g., DMAP, followed by addition of a fatty acid of Formula C affords compounds of Formula CCC. The ester may be deprotected using methods disclosed in Greene, et al. <i>Protecting Groups in Organic Chemistry. </i>4^thed. Wiley &amp; Sons, Hoboken, N.J. (2007). See, e.g., Chapter 5, therein.

2246<chemistry id="CHEM-US-00644" num="00644"><img file="US8729293B2_D0644.tif" /></chemistry><br /> wherein r and s are as defined for Formula III.

2247Compound TT can be esterified in the presence of acid catalyst and a suitable protecting alcohol such as, e.g., methanol, followed by coupling to an activated amino acid to give compound DDD. Condensation of the amino compound DDD with a fatty acid chloride of Formula G affords compounds of Formula EEE. The ester may be deprotected using methods disclosed in Greene, et al. <i>Protecting Groups in Organic Chemistry. </i>4^thed. Wiley &amp; Sons, Hoboken, N.J. (2007). See, e.g., Chapter 5, therein.

EXAMPLES

2248The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.

Example 1

Effect of Illustrative Compounds of the Invention on Inflammatory Activity in Adipose Tissue in Mice

2249Demonstration of the ability of illustrative Compounds of the Invention to mediate serum adiponectin concentrations in a rodent obesity model was shown using methods described in Itoh, M., et al., <i>Arterioscler. Thromb. Vasc. Biol. </i>2007 27(9):1918-25. Male C57BL/6J ob/ob mice and their wild-type (WT) littermates are purchased from Charles River Laboratories (Wilmington, Mass.). The animals are housed in individual cages in a temperature-, humidity-, and light-controlled room (12-hour light and 12-hour dark cycle) and allowed free access to water and fish meal-free diet (fish meal-free F1 (Funabashi Farm, Chiba, Japan) supplemented with; 362 kcal/100 g, 4.4% energy as fat).

2250Six-week-old male ob/ob mice and WT littermates are allowed unrestricted access to the fish meal-free diet (control group) or fish meal-free diet supplemented with 5% EPA (wt/wt) (EPA-treated group) for 4 weeks (n=10 to 14). In the short-term administration protocol, 8-week-old male ob/ob mice are treated with the Compound of the Invention for 2 weeks (n=7 to 8). All diets are changed every day and served with nonmetallic feeder to prevent oxidization of fatty acids. At the end of the experiments, mice are euthanized after 5-hour starvation under intraperitoneal pentobarbital anesthesia (30 mg/kg). Blood glucose and serum concentrations of triglyceride (TG) and free fatty acid (FFA) are measured as described in Kouyama R, et al., <i>Endocrinology, </i>146: 3481-3489, 2005. Serum fatty acid and salicylate concentrations are measured by gas chromatography.

Example 2

In Vivo Effects of Compounds of the Invention in Zucker Fatty Rats and ob/ob Mice

2251Twelve-week-old male Zucker fa/fa rats and 8-week-old ob/ob (Lepob/ob) and ob/1 mice are given free access to food and water. A Compound of the Invention (120 mg/kg/day) is dosed orally by gavage once per day. For glucose tolerance tests, glucose (2.0 g/kg) is administered by oral gavage (rats) or intraperitoneal injection (mice) after an overnight fast. Blood glucose and serum insulin concentrations are determined during oral glucose tolerance tests in Zucker fa/fa rats or fa/1 rats. For insulin tolerance tests, insulin (2.0 U/kg) is injected intraperitoneally after an overnight fast. Cholesterol, triglyceride, long-chain FFA, and ALT concentrations are measured in sera from fasting Zucker fa/fa rats.

Example 3

Effects of Compounds of the Invention on Insulin Signaling in 3T3-L1 Adipocytes

22523T3-L I adipocytes are serum starved for 16 hours and treated or not treated with 5 mM aspirin for 2 hours and either 6.0 nM mTNFα (20 min) or the phosphatasen inhibitor calyculin A (Axxora, San Diego, USA) (at 2.0 nM for 30 min) as described in Yuan, M., et al., <i>Science, </i>293, 1673-1677, 2001. After a 5-min stimulation with 10 nM insulin, the cells are chilled and solubilized and proteins are immunoprecipitated with anti-IR or anti-IRS1. Proteins are separated by SDS-PAGE and identified by Western blotting with anti-pY, anti-IR, or anti-IRS1.

Example 4

Effects of Compounds of the Invention on IL-10 Levels in 3T3-L1 Adipocytes

2253IL-10 production in 3T3-L1 adipocytes is measured using a modification of the method described by Bradley et al, <i>Obesity </i>(2008) 16, 938-944. Fully differentiated 3T3-L1 adipocytes are serum starved for 18 hours in DMEM containing 0.2% fatty acid free bovine serum albumin (BSA) and 0.1 mM pyruvate. A stock of 5 mM test compound is prepared in 100% ethanol and then is diluted 1:100 in 2% fatty acid free BSA in DMEM (with 0.1 mM pyruvate), yielding a 50 μM solution of compound. Starvation media is removed from cells and is replaced by the 50 μM compound solution in DMEM or Vehicle (0.1% ethanol, 0.2% fatty acid free BSA in DMEM with 0.1 mM pyruvate). Test compound or Vehicle is incubated with cells for 48 hours. Subsequently, RNA is purified from cells and reverse transcribed to cDNA. IL-10 message levels are then measured by quantitative real-time PCR (Applied Biosystems Step-One) using gene-specific oligonucleotide primers and fluorescently labeled probe. IL-10 levels are normalized to the house-keeping gene GAPDH, which was measured using the same method. IL-10 levels in Compound of the Invention treated samples are expressed as a fold increase over IL-10 levels in Vehicle treated samples. (**p&lt;0.005 by 2-tailed t-test). A sample graph showing the data obtained by using one of the Compounds of the Invention described above in Example 4 is shown in <figref idref="DRAWINGS">FIG. 1</figref>.

Example 5

Effects of Compounds of the Invention in Fao Hepatoma Cells

2254Fao cells are serum starved for 16 hours followed by 2-hour incubations at 37° C. with mM-25 mM a Compound of the Invention according to the method described in Yuan, M., et al., <i>Science, </i>293, 1673-1677, 2001. Cells are then stimulated sequentially with 6.0 nM mTNFα for 20 min. and 10 nM insulin for 5 min. Cells are chilled and solubilized and proteins are then immunoprecipitated with anti-IR and detected by Western blotting using anti-pY. Phosphorylation is quantified by densitometry.

Example 6

TNFα Release Assay in RAW 264.7 Macrophages

2255The purpose of this assay is to measure the ability of small molecules to inhibit the secretion of TNFα in cultured macrophages stimulated with lipopolysaccharide (LPS). Treatment of macrophages with LPS activates inflammatory cytokine pathways primarily through the TLR4-NFκB signaling axis. Compounds of the Invention inhibit the transcriptional activation of NFκB and thus decrease the production and release of TNFα. Dexamethasone, a potent agonist of the glucocorticoid receptor is used a positive control for inhibition of TNFα release.

2256Day 1: Seed RAW 264.7 macrophages into 96 well culture plates. Remove culture media from RAW 264.7 cell growing in a 75 mm²tissue culture flask (cells should be at ˜70% confluence) and add 10 ml of warmed complete growth media (DMEM+10% FBS+1× pen/step). The cells are scraped into suspension using a sterile plate scraper and homogenized by pipetting up and down with a 10 ml serological pipette. The cell concentration is determined using a clinical hematoctyometer. Cells are then diluted to 150,000 cells per ml into growth media. The diluted cells are then transferred to a sterile reagent reservoir and 100 μl of cell suspension is pipetted into each well of a 96 well culture plate using a multichannel pipette (15,000 cells/well). Plates are then incubated at 37° C. under normal tissue culture growth conditions (37° C., humidified CO₂chamber).

2257Day 2: The test compound sample plate is prepared. Test compounds are prepared in growth media. Compounds are delivered to media from 1000× stocks in 100% DMSO (e.g. for a 10 μM final concentration of test compound, deliver 2 μl of 10 mM test compound to 2 ml of media). At least 150 μl of 1× compound in media is added to 96 well sample plate. Note: the perimeter wells of the 96 well plate are not used to avoid edge effects. Twelve sample wells are prepared with media plus 0.1% DMSO (these samples will serve as the vehicle controls; LPS-stimulated and non-stimulated. 10 μM dexamethasone is used as a positive control). Culture plates are then returned to the growth incubator for 2 hours. Cells are stimulated afterwards by adding 25 μl of 50 ng/ml LPS is added to every well (except the 6 unstimulated vehicle control wells: final concentration of 10 ng/ml LPS. Plates are returned to growth incubator for 3 hours. Afterwards, 100 μl of media supernatant is removed and transferred to a 96 well v-bottom sample plate. The media supernatant plate is centrifuged for 5 minutes at 1000 rpm in a swing-bucket centrifuge, pelleting any cellular debris that may remain in supernatant. 80 μl of supernatant is removed from sample plate and transferred to a fresh v-bottom 96 well plate. Cell viability is measured using Celltiter-glo kit. By measuring cell viability, a given compound's effects on TNFα secretion can determine whether effects are due to cytotoxicity or to true inhibition of inflammatory signaling. Add 100 μl of Celltiter-glo reagent to each well of the cell culture plate and afterwards measure the luminescence signal (CPS) of the plate using the Victor 5 plate reader (0.3 second read; 60 second plate shaking prior to read). Cell viability of a given compound at a given concentration is computed as follows: <br />Cell viability=CPS Sample/(Average CPS unstimulated controls)*100

2258Use 20 μl of media supernatant per well for TNFα ELISA. Follow Invitrogen/Biosource manufacture's protocol for the mouse TNFα ELISA. Chromogen development is typically conducted for 20-30 minutes as described in the manufacturer's protocol. After addition of stop solution, measure OD 450 nm using the Victor 5 plate reader (0.1 second/well scan). Determine the TNFα secretion percent of control. The following formula is used to determine the TNFα secretion percent of control:

2259<maths id="MATH-US-00001" num="00001"><math overflow="scroll"><mfrac><mtable><mtr><mtd><mrow><mrow><mn>100</mn><mo>×</mo><mrow><mo>(</mo><mrow><mi>OD</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mn>450</mn><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>nm</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>Sample</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>X</mi></mrow><mo>)</mo></mrow></mrow><mo>-</mo></mrow></mtd></mtr><mtr><mtd><mrow><mo>(</mo><mrow><mi>Average</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>OD</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mn>450</mn><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>nm</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>unstimulated</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>vehicle</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>controls</mi></mrow><mo>)</mo></mrow></mtd></mtr></mtable><mtable><mtr><mtd><mrow><mrow><mo>(</mo><mrow><mi>Average</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>OD</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mn>450</mn><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>nm</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>LPS</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>stimulated</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>vehicle</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>controls</mi></mrow><mo>)</mo></mrow><mo>-</mo></mrow></mtd></mtr><mtr><mtd><mrow><mo>(</mo><mrow><mi>Average</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>OD</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mn>450</mn><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>nm</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>unstimulated</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>vehicle</mi><mo>⁢</mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo>⁢</mo><mi>controls</mi></mrow><mo>)</mo></mrow></mtd></mtr></mtable></mfrac></math></maths><img file="US8729293B2_D0645.tif" />

2260For each test compound, TNFα secretion percent of control can be plotted as a function of compound concentration using a four parameter dose-response curve fit equation (XLFIT Model #205): <br />fit=(<i>A</i>+((<i>B−A</i>)/(1+((<i>C/x</i>)^<i>D</i>))))<br />inv=(<i>C</i>/((((<i>B−A</i>)/(<i>y−A</i>))−1)^(1<i>/D</i>)))<br />res=(<i>y</i>−fit)

2261For compounds which cause greater than 50% inhibition of TNFα secretion, determine the IC₅₀(concentration of compound which causes 50% inhibition of TNFα secretion). A sample graph showing the data obtained by using one of the Compounds of the Invention in the procedure described above in Example 6 is shown in <figref idref="DRAWINGS">FIG. 2</figref>.

2262As seen in <figref idref="DRAWINGS">FIG. 2</figref>, salicylate alone, fatty acid alone, and the simple combination of salicylate and fatty acid administered together do not appreciably inhibit the production of TNFα. In contrast the fatty acid acetylated salicylate significantly inhibits the production of TNFα. This demonstrates that the fatty acid acetylated salicylate is the species responsible for the inhibition of TNFα production and not either of the individual components alone or in simple combination.

2263A sample table showing the data obtained by using additional Compounds of the Invention in the procedure described above in Example 6 is shown in Table 1, below:

2264<tables id="TABLE-US-00001" num="00001"><table frame="none" colsep="0" rowsep="0"><tgroup align="left" colsep="0" rowsep="0" cols="3"><colspec colname="1" colwidth="28pt" align="left" /><colspec colname="2" colwidth="49pt" align="center" /><colspec colname="3" colwidth="140pt" align="center" /><thead><row><entry namest="1" nameend="3" rowsep="1">TABLE 1</entry></row><row><entry namest="1" nameend="3" align="center" rowsep="1" /></row><row><entry /><entry>Compound</entry><entry>TNF□ Secrection,</entry></row><row><entry /><entry>Number</entry><entry>IC₅₀uM</entry></row><row><entry namest="1" nameend="3" align="center" rowsep="1" /></row></thead><tbody valign="top"><row><entry /></row></tbody></tgroup><tgroup align="left" colsep="0" rowsep="0" cols="3"><colspec colname="1" colwidth="28pt" align="left" /><colspec colname="2" colwidth="49pt" align="center" /><colspec colname="3" colwidth="140pt" align="char" char="." /><tbody valign="top"><row><entry /><entry>Ia-1</entry><entry>69.2</entry></row><row><entry /><entry>III-1</entry><entry>145.6</entry></row><row><entry /><entry>Ic-1</entry><entry>NT</entry></row><row><entry /><entry>31</entry><entry>15.0</entry></row><row><entry /><entry>5ASA</entry><entry>>100</entry></row><row><entry /><entry>32</entry><entry>NT</entry></row><row><entry /><entry>DHA</entry><entry>>100</entry></row><row><entry /><entry>III-6</entry><entry>65.3</entry></row><row><entry /><entry>I-1</entry><entry>24.4% Inhibition at 6.2 uM</entry></row><row><entry namest="1" nameend="3" align="center" rowsep="1" /></row></tbody></tgroup></table></tables>

Example 7

In Vivo Effects of Compounds of the Invention in an LPS-Challenge TNFα Mouse Model

2265To measure the effects of compounds on TNFα secretion in vivo, Male Swiss Webster mice (n=10 animals per group) are dosed by oral gavage with each test compound. All compounds are formulated in an aqueous solution of 0.5% carboxymethylcellulose and 0.05% TWEEN-80 (Vehicle). One hour after compound dosing, animals are treated with 0.2 mg/kg LPS (lipopolysaccharide) by intraperitoneal (IP) injection. Ninety minutes after LPS challenge, mice are anesthetized and bled by cardiac puncture into serum separator tubes (with sodium heparin). Bleeds are allowed to clot at room temperature for 2 hours, and tubes are then spun for 20 minutes at 2000×g. Serum is harvested from tubes (100-150 μl per animal) and frozen at −70° C. TNFα serum levels are measured using commercially available TNFα ELISA kits. (*p&lt;0.05 using a 2-tailed t-test). A sample graph showing the data obtained by using some of the Compounds of the Invention in the procedure described above in Example 7 is shown in <figref idref="DRAWINGS">FIG. 3</figref>.

Example 8

Effects of Compounds of the Invention on NFκB Levels in RAW 264.7 Macrophages

2266RAW 264.7 cells transfected with an NFκB-driven luciferase reporter are plated in 96 well plates. Cells are treated with Vehicle (0.1% ethanol) or test compounds for 2 hours. As a positive control for inhibition of NFκB signaling, 6 wells are treated with 10 μM dexamethasone. Cells are then challenged with 200 ng/ml LPS for 3 hours in the presence of test compounds. A subset of wells treated with vehicle should remain unstimulated with LPS to determine the floor signal of the assay. NFκB driven luciferase activity is developed by addition of BriteLite luciferase kit (Perkin-Elmer) and measured using a Victor V plate reader. NFκB activity (luciferase activity) for each treatment was normalized to Vehicle wells treated with LPS (% NfκB Response). AlamarBlue was used to monitor cell viability to ensure that inhibition of luciferase signal was not a result of compound cytotoxicity.

2267A sample table showing the data obtained by using additional Compounds of the Invention in the procedure described above in Example 8 is shown in Table 2, below:

2268<tables id="TABLE-US-00002" num="00002"><table frame="none" colsep="0" rowsep="0"><tgroup align="left" colsep="0" rowsep="0" cols="3"><colspec colname="1" colwidth="35pt" align="left" /><colspec colname="2" colwidth="49pt" align="center" /><colspec colname="3" colwidth="133pt" align="center" /><thead><row><entry namest="1" nameend="3" rowsep="1">TABLE 2</entry></row><row><entry namest="1" nameend="3" align="center" rowsep="1" /></row><row><entry /><entry>Compound</entry><entry>NFκB Inhibitory</entry></row><row><entry /><entry>Number</entry><entry>Activity, IC₅₀μM</entry></row><row><entry namest="1" nameend="3" align="center" rowsep="1" /></row></thead><tbody valign="top"><row><entry /><entry>Ia-1</entry><entry>−</entry></row><row><entry /><entry>III-1</entry><entry>++++</entry></row><row><entry /><entry>3</entry><entry>+++</entry></row><row><entry /><entry>Ic-1</entry><entry>−</entry></row><row><entry /><entry>31</entry><entry>++++</entry></row><row><entry /><entry>32</entry><entry>−</entry></row><row><entry /><entry>III-6</entry><entry>++</entry></row><row><entry /><entry>I-1</entry><entry>++++</entry></row><row><entry /><entry>9</entry><entry>+++</entry></row><row><entry /><entry>10</entry><entry>++</entry></row><row><entry /><entry>11</entry><entry>+++</entry></row><row><entry /><entry>12</entry><entry>+++</entry></row><row><entry /><entry>13</entry><entry>++++</entry></row><row><entry /><entry>14</entry><entry>++++</entry></row><row><entry /><entry>15</entry><entry>+++</entry></row><row><entry /><entry>16</entry><entry>−</entry></row><row><entry /><entry>17</entry><entry>++</entry></row><row><entry /><entry>18</entry><entry>−</entry></row><row><entry /><entry>19</entry><entry>−</entry></row><row><entry /><entry>20</entry><entry>−</entry></row><row><entry /><entry>21</entry><entry>−</entry></row><row><entry /><entry>22</entry><entry>+++</entry></row><row><entry /><entry>23</entry><entry>−</entry></row><row><entry /><entry>24</entry><entry>++</entry></row><row><entry /><entry>5-ASA</entry><entry>−</entry></row><row><entry /><entry>DHA</entry><entry>−</entry></row><row><entry /><entry>DHA + SA</entry><entry>−</entry></row><row><entry /><entry>SA</entry><entry>−</entry></row><row><entry namest="1" nameend="3" align="center" rowsep="1" /></row><row><entry namest="1" nameend="3" align="left" id="FOO-00001">A − indicates that the compound showed no inhibitory activity. A + indicates that the compound showed inhibitory activity. A greater number of +'s indicates a higher level of inhibitory activity.</entry></row></tbody></tgroup></table></tables>

Compounds

2269The following non-limiting compound examples serve to illustrate further embodiments of the Compounds of the Invention. It is to be further understood that any embodiments listed in the Examples section are embodiments of the Compounds of the Invention and, as such, are suitable for use in the methods and compositions described above.

Example 9

Preparation of 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)benzoic acid (Ia-1)

2270<chemistry id="CHEM-US-00645" num="00645"><img file="US8729293B2_D0646.tif" /></chemistry>

2271To a mixture of DHA (6.0 g, 18.3 mmol) in dichloroethane (30 mL) and DMF (0.05 mL) was slowly added oxalyl chloride (5.0 mL, 56.9 mmol). The reaction mixture was stirred (RT, 2 h) and concentrated under reduced pressure to obtain DHA-Cl as a yellow liquid. To a mixture of salicylic acid (3.78 g, 27.4 mmol) and NEt₃(3.80 mL, 27.5 mmol) in dichloroethane (35 mL) at 0° C. was slowly added the DHA-Cl in dichloroethane (35 mL). The reaction mixture was stirred (RT, 16 h), washed with 1N HCl and brine, dried over MgSO₄, filtered and concentrated under reduced pressure. The crude material was purified by silica chromatography (PE-EtOAc, 19:1) to afford 2-(docosa-4,7,10,13,16,19-hexaenoyloxy)benzoic acid (5.83 g, 71%) as a light yellow oil. Mass calculated for C₂₉H₃₆O₄=448.59. found: [M−H]⁺=447.7.

Example 10

Preparation of 5-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-2-hydroxybenzoic acid (III-1)

2272<chemistry id="CHEM-US-00646" num="00646"><img file="US8729293B2_D0647.tif" /></chemistry>

2273To a solution of saturated HCl in CH₃OH (20 mL) at RT was slowly added 5-amino-2-hydroxybenzoic acid (2 g, 13.06 mmol). The resulting mixture was stirred at (RT, 16 h) and then heated (reflux, 24 h). The mixture was cooled and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO₃. The organic solution was dried over MgSO₄, filtered, concentrated under reduced pressure to afford methyl 5-amino-2-hydroxybenzoate as a pale yellow solid (1.72 g, 78.5%). Mass calculated for C₈H₉NO₃=167.16. found: [M+H]⁺=168.2.

2274To a mixture of methyl 5-amino-2-hydroxybenzoate (52.9 mg, 0.317 mmol), DHA (100 mg, 0.305 mmol) and Et₃N (61.7 mg, 0.61 mmol) in CH₃CN (2 mL) was added HATU (120 mg, 0.260 mmol). The mixture was stirred (RT, 4.5 h). The solvent was removed under reduced pressure and the residue was extracted with EtOAc (4×20 mL). The combined organic layer was washed with 1N aq. HCl, water, 5% NaHCO₃, water, and dried over MgSO₄. The solvent was removed under reduced pressure. The crude product was purified by silica chromatography (EtOAc:PE, 1:10 to 2:3) to afford methyl 5-docosa-4,7,10,13,16,19-hexaenamido-2-hydroxybenzoate (3) as a light yellow oil (104.5 mg, 72.1%). Mass calculated for C₃₀H₃₉NO₄=477.63. found: [M+H]⁺=478.5.

2275A mixture of methyl 5-docosa-4,7,10,13,16,19-hexaenamido-2-hydroxybenzoate (0.1 g, 0.2 mmol) in 2N NaOH (5 mL) and CH₃OH (2.5 mL) was stirred (50° C., 24 h). The mixture was cooled and acidified to pH 1 with 2N aq. HCl, then extracted with EtOAc (3×10 mL). The organic layer was washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (CH₂Cl₂-EtOAc, 20:1 to 1:1) to afford 5-docosa-4,7,10,13,16,19-hexaenamido-2-hydroxybenzoic acid as a white solid (90.4 mg, yield: 90%). Mass calculated for C₂₉H₃₇NO₄=463.61. found: [M+H]⁺=464.3.

Example 11

Preparation of 3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropyl 2-acetoxybenzoate (Ic-1)

2276<chemistry id="CHEM-US-00647" num="00647"><img file="US8729293B2_D0648.tif" /></chemistry>

2277To a mixture of 3-aminopropan-1-ol (5.0 g, 67 mmol), Na₂CO₃(8.8 g, 83 mmol) in THF (40 mL) and H₂O (130 mL) at 0° C. was added Cbz-Cl (14.8 g, 87 mmol). The reaction mixture was stirred (RT, 1 h). Water (500 mL) and CH₂Cl₂(500 mL) were added, and the layers were separated. The organic layer was dried over MgSO₄and concentrated under reduced pressure. The residue was purified by silica chromatography (PE:EA, 5:1) to afford benzyl 3-hydroxypropylcarbamate as a white solid (12.6 g, 90.5%).

2278To a solution of 2-acetoxybenzoic acid (2.0 g, 11.1 mmol) and triethylamine (1.8 mL, 11.1 mmol) in CH₂Cl₂(40 mL) at 0° C. was slowly added ClCO₂Et (1.1 mL, 167 mmol). The reaction mixture was stirred (0° C., 2 h) and filtered. The filtrate was added to a solution of benzyl 3-hydroxypropylcarbamate (2.1 g, 10.0 mmol) and triethylamine (15 mL) in CH₂Cl₂(40 mL). The reaction mixture was stirred (RT, 4 h) and quenched with H₂O (50 mL). The organic layer was washed with 1 M HCl, saturated Na₂CO₃(30 mL) and H₂O (50 mL). The organic solution was dried over MgSO₄and concentrated under reduced pressure. The residue was purified by silica chromatography, (PE-EtOAc, 5:1) to afford 3-(benzyloxycarbonylamino)propyl 2-acetoxybenzoate (2.0 g, 54%) as a colorless oil. Mass calculated for C₂₀H₂₁NO6₄=371.38. found: [M+H]⁺=372.3.

2279A mixture of 3-(benzyloxycarbonylamino)propyl 2-acetoxybenzoate (2.0 g, 5.4 mmol), 10% Pd/C (0.2 g) and CH₃OH (50 mL) was stirred under a H₂atmosphere (RT, 16 h). The mixture was filtered and concentrated under reduced pressure to afford a colorless oil. Purification by silica chromatography afforded 3-aminopropyl 2-acetoxybenzoate as a colorless oil. Mass calculated for C₁₂H₁₅NO₄=237.25. found: [M+H]⁺=238.3.

2280To a solution of DHA (500 mg, 1.52 mmol) in ClCH₂CH₂Cl (10 mL) and one drop of DMF at 0° C. was slowly added oxalyl chloride (0.3 mL, 3.42 mmol). The reaction mixture was stirred (RT, 2 h) and concentrated under reduced pressure. The residue was treated with toluene (5 mL) and the solvent was removed under reduced pressure to obtain the DHA acid chloride as a yellow liquid. To a solution of 3-aminopropyl 2-acetoxybenzoate (360 mg, 1.52 mmol) and NEt₃(0.36 g, 3.56 mmol) in ClCH₂CH₂Cl (10 mL) at 0° C. was added a solution of DHA-acid chloride in ClCH₂CH₂Cl. The reaction mixture was stirred (0° C., 2 h, then warmed to RT, 12 h). Purification by silica chromatography afforded 3-docosa-4,7,10,13,16,19-hexaenamidopropyl 2-acetoxybenzoate. Mass calculated for C₃₄H₄₅NO₅=547.72. found: [M+H]⁺=548.3.

Example 12

Preparation of N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide (31)

2281<chemistry id="CHEM-US-00648" num="00648"><img file="US8729293B2_D0649.tif" /></chemistry>

2282Ethylenediamine (1.0 g, 16.7 mmol) is dissolved in water (3.0 mL) containing bromoaresal green as an indicator. Methane sulfonic acid (2.8 g, 31 mmol) in water (3.0 ml) was added until a blue to pale yellow color transition is just achieved. The solution was diluted with ethanol (8.0 mL) and vigorously stirred. To the mixture was added the solution of Cbz-Cl (2.8 g, 16.7 mmol) in dimethoxyethane (4 mL) and 50% w/v aqueous AcOK (10 mL) at 20° C. simultaneously to maintain the pale yellow-green color of the indicator. After the additions are complete the mixture was stirred (RT, 1 h) and concentrated at low temperature under vacuum to removed the volatiles. The residue was shaken with water (20 mL) and filtered. The filtrate was then washed with toluene (3×50 mL), basified with excess 40% aqueous NaOH and extracted with toluene (3×50 mL). The organic layer was washed with brine (50 mL), dried over Na₂SO₄and evaporated to give benzyl 2-aminoethylcarbamate as an oil (1.65 g, 51%). Mass calculated for C₁₀H₁₄N₂O₂=194.23. found: [M−H]⁺=193.3.

2283To a mixture of benzyl 2-aminoethylcarbamate (1.65 g, 8.5 mmol), imidazole (0.58 g, 8.5 mmol), salicylic acid (1.73 g, 8.5 mmol) in ethyl acetate (30 mL) was added a solution of DCC (1.75 g, 8.5 mmol) in ethyl acetate (50 mL). The mixture was stirred (RT, 16 h) and filtered. The solution was concentrated under reduced pressure and the crude product was purified by silica chromatography (EtOAc:PE, 0-50%) to afford benzyl 2-(2-hydroxybenzamido)ethylcarbamate as a white solid (1.84 g, 66%). Mass calculated for C₁₇H₁₈N₂O₄=314.34. found: [M+H]⁺=315.2.

2284A mixture of benzyl 2-(2-hydroxybenzamido)ethylcarbamate (1.84 g, 5.86 mmol) and Pd/C (0.18 g) in MeOH (30 mL) was stirred under a H₂atmosphere (16 h). The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica chromatography (EtOAc-MeOH—NH₃OH (5:1:0.01) to afford N-2-(aminoethyl)-2-hydroxybenzamide as a white powder (0.68 g, 65%). Mass calculated for C₀H₁₂N₂O₂=180.20. found: [M+H]⁺=181.2.

2285To a mixture of N-2-(aminoethyl)2-hydroxybenzamide (58 mg, 0.32 mmol), DHA (100 mg, 0.3 mmol) and Et₃N (0.1 ml, 0.7 mmol) in CH₃CN (2 mL) was added HATU (115 mg, 0.3 mmol). The mixture was stirred (RT, 24 h) and concentrated under reduced pressure. The residue was treated with brine (15 mL); and extracted with EtOAc (3×30 mL). The combined organic layers were washed with 1M HCl, brine, 5% NaHCO₃and brine. The organic solution was dried over MgSO₄and concentrated under reduced pressure. The crude product was purified by silica chromatography (EtOAc:PE, 1:1) to afford N-(2-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide (94 mg, 64%) as light yellow oil. Mass calculated for C₃₁H₄₂N₂O₃=490.68. found: [M+H]⁺=491.4.

Example 13

Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-1-(4-(2-hydroxybenzoyl)piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (32)

2286<chemistry id="CHEM-US-00649" num="00649"><img file="US8729293B2_D0650.tif" /></chemistry>

2287To a mixture of tert-butylpiperazine-1-carboxylate (0.57 g, 3.05 mmol), DHA (1 g, 3.05 mmol) and Et₃N (0.61 g, 6.1 mmol) in CH₃CN (20 mL) was added HATU (1.16 g, 3.05 mmol). The mixture was stirred (RT, 16 h). The solvent was removed under reduced pressure and the residue was extracted with EtOAc (4×30 mL). The combined organic layers were washed successively with 1N aqueous HCl, water, 5% NaHCO₃and water, and dried over MgSO₄. The solvent was removed under reduced pressure and the crude product was purified by silica chromatography (EA-PE, 1:10 to 1:1) to afford tert-butyl 4-docosa-4,7,10,13,16,19-hexaenoylpiperazine-1-carboxylate (1.5 g, 99%) as a colorless oil. Mass calculated for C₃₁H₄₈N₂O₃=496.72. found: [M+H]⁺=497.6.

2288To a mixture of tert-butyl 4-docosa-4,7,10,13,16,19-hexaenoylpiperazine-1-carboxylate (1.5 g, 3 mmol) in CH₂Cl₂(20 mL) at 0° C. was added CF₃CO₂H (7 mL, 91 mmol). The mixture solution was stirred (0° C., 2 h) and then 10% Na₂CO₃was added to adjust pH=10. The mixture was extracted with CH₂Cl₂(3×30 mL). The combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure. The crude product was purified by silica chromatography (CH₂Cl₂:CH₃OH, 20:1) to afford 1-(piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (1.17 g, 97.5%) as a colorless oil. Mass calculated for C₂₆H₄₀N₂O=396.61. found: [M+H]⁺=396.7, 398.2.

2289To a mixture of 1-(piperazin-, 1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (1.17 g, 2.95 mmol), salicylic acid (0.61 g, 4.43 mmol) and Et₃N (0.89 g, 8.85 mmol) in CH₃CN (10 mL) was added HATU (L68 g, 4.43 mmol). The mixture was stirred (RT, 16 h). The solvent was removed under reduced pressure and the residue was extracted with EtOAc (4×50 mL). The combined organic layers were washed successively with 1N aqueous HCl, water, 5% NaHCO₃and water, and dried over MgSO₄. The solvent was removed under reduced pressure. Purification of the crude product by prep-HPLC afforded 1-(4-(2-hydroxybenzoyl)piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (300 mg, 19.6%) as a light yellow oil. Mass calculated for C₃₃H₄₄N₂O₃=516.71. found: [M+H]⁺517.6.

Example 14

Preparation of 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoic acid (III-6)

2290<chemistry id="CHEM-US-00650" num="00650"><img file="US8729293B2_D0651.tif" /></chemistry>

2291A mixture of 2-(benzyloxycarbonylamino)-4-methylpentanoic acid (1 g, 3.8 mmol), methyl 5-amino-2-hydroxybenzoate (0.66 g, 3.95 mmol) and Et₃N (0.76 g, 7.6 mmol) were dissolved in CH₃CN (10 mL) and HATU (1.503 g, 3.95 mmol) was added. The mixture was stirred (RT, 16 h). The solvent was removed under reduced pressure. Brine (50 mL) was added to the resulting residue, and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed successively with 2N aq. HCl (3×50 mL), brine (50 mL), 5% NaHCO₃(50 mL×3), brine (50 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude material was purified by silica chromatography on (CH₂Cl₂) to give methyl 5-(2-(benzyloxycarbonylamino)-4-methylpentanamido)-2-hydroxybenzoate as a white solid (0.81 g, 51.8%).

2292The mixture of 5-(2-(benzyloxycarbonylamino)-4-methylpentanamido)-2-hydroxybenzoate (0.81 g, 1.9 mmol) and 0.1 g Pd/C in MeOH (15 mL) was stirred under H₂(RT, 16 h). The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica chromatography (MeOH/DCM, 0 to 5%)) to afford methyl 5-(2-amino-4-methylpentanamido)-2-hydrozybenzoate as a white solid (0.53 g, 90%). Mass calculated for C₁₄H₂₀N₂O₄=280.32. found: [M+H]⁺=281.2.

2293To a solution of methyl 5-(2-amino-4-methylpentanamido)-2-hydrozybenzoate (85 mg, 0.30 mmol), DHA (100 mg, 0.30 mmol), Et₃N (0.1 ml 0.71 mmol) in CH₃CN (2 mL) was added HATU (114 mg, 0.30 mmol). The mixture was stirred (RT, 16 h) and the solvent was removed under reduced pressure. The residue was diluted with brine (20 mL) and extracted with ethyl acetate (50 mL). The combined organic layer was washed with 1M HCl (20 mL), brine (20 mL), 5% aq. NaHCO₃(20 mL) and brine (20 mL), dried over MgSO₄, and concentrated under reduced pressure. The crude product was purified by silica chromatography (EtOAc/DCM, 0 to 10%) to afford methyl 5-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoate as light yellow oil. (155 mg, 87%). Mass calculated for C₃₆H₅₀N₂O₅=590.79. found: [M+H]⁺=591.6.

2294To a solution of methyl 5-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoate (155 mg, 0.26 mmol) in MeOH (3 mL) was added 2M NaOH (5 mL). The mixture was heated (45-50° C., 16 h), and then cooled to RT. 2M HCl was added dropwise to adjust pH=1. The mixture was then extracted by EA (3×20 mL). The combined organic layers were washed with brine, dried over MgSO₄and concentrated under reduced pressure. The crude product was purified by silica chromatography (MeOH/DCM, 0-10%) to afford of 5-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoic acid as light yellow oil (92 mg, 61%). Mass calculated for C₃₅H₄₈N₂O₅=576.77. found: [M+H]⁺=577.3.

Example 15

Preparation of ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate (I-1)

2295<chemistry id="CHEM-US-00651" num="00651"><img file="US8729293B2_D0652.tif" /></chemistry>

22962-Amino-4-methylpentanoic acid (5.0 g 38.2 mmol) was slowly added to sat. HCl/MeOH (50 mL). The mixture was stirred (RT, 5 h) then heated to reflux (16 h). After the reaction, the solvent was removed under reduced pressure. The residue was diluted with water (50 mL), then NaHCO₃was added to adjust pH=7. The mixture was then extracted with DCM (3×50 mL), the combined organic layers were dried over MgSO₄, concentrated under reduced pressure to afford methyl 2-amino-4-methylpentanoate as a colorless liquid (5.3 g, 96%). Mass calculated for C₇H₁₅NO₂=145.20. found: [M+H]⁺=145.9. The product was used in next step without further purification.

2297To a solution of methyl 2-amino-4-methylpentanoate (250 mg, 1.6 mmol), DHA (510 mg, 1.5 mmol), Et₃N (0.42 mL, 3 mmol) in CH₃CN (20 mL) at RT was added HATU (570 mg, 1.5 mmol). The mixture was stirred (RT, 16 h) and the solvent was removed under reduced pressure. The residue was diluted with brine and extracted with EtOAc. The organic layer was washed with 1M HCl (50 mL), brine (50 mL), 5% NaHCO₃(50 mL) and brine (50 mL). The organic solution was dried over MgSO₄and concentrated under reduced pressure. The crude product was purified by silica chromatography (EtOAc:PE, 0-25%) to afford methyl 2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoate (0.61 g, 85%) as a light yellow oil. Mass calculated for C₂₉H₄₅NO₃=455.67. found: [M+H]⁺=456.2.

2298To a solution of methyl 2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoate (610 mg, 1.34 mmol) in MeOH (15 mL) was added 2 M NaOH (30 mL). The reaction mixture was heated (50° C., 16 h), cooled (RT), and acidified with 2 M HCl to pH=1. The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The crude product was purified by silica chromatography, (MeOH:DCM, 0-10%) to afford 2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoic acid (0.51 g, 89%) as a light yellow solid. Mass calculated for C₂₈H₄₃NO₃=441.65. found: [M+H]⁺=442.1.

2299To a solution of 2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoic acid (50 mg, 0.11 mmol) and ethyl 2-hydroxybenzoate (19 mg, 0.11 mmol) in CH₃CN/THF (1:1, 0.5 mL) at −10° C. was added DCC (12 mg, 0.11 mmol) and DMAP (1 mg). The mixture, was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude product was purified by silica chromatography (EtOAc-PE, 0-20%) to afford ethyl 2-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate (40 mg, 67%) as colorless oil. Mass calculated for C₃₇H₅₁NO₅=589.80. found: [M+H]⁺=590.4.

Example 16

Preparation of 1-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)ethyl 2-acetoxybenzoate (9)

2300<chemistry id="CHEM-US-00652" num="00652"><img file="US8729293B2_D0653.tif" /></chemistry>

2301To a solution of compound 2-acetoxybenzoic acid (1.0 g, 5.5 mmol) in THF (30 mL) was added (COCl)₂(0.8 ml, 9.1 mmol) at 0° C. The mixture was heated (reflux, 1.5 h) and concentrated under reduced pressure to afford 2-(chlorocarbonyl)phenyl acetate.

2302To a mixture of 2,4,6-trimethyl-1,3,5-trioxane (245 mg, 1.85 mmol) and NaI (0.972 g, 6.48 mmol) in DCM (15 mL) was added a solution of 2-(chlorocarbonyl)phenyl acetate in DCM (5 mL, 0° C.). The resulting mixture was allowed to stir (RT, 16 h). The mixture was filtrated and concentrated under reduced pressure. The crude was purified by silica chromatography (EtOAc-PE, 0-10%) to afford 1-iodoethyl 2-acetoxybenzoate (0.75 g, 40%) as a light yellow oil:

2303To a solution of DHA (0.1 g, 0.3 mmol) in CH₃CN (1 mL) was added K₂CO₃(41.4 mg, 0.3 mmol) followed by Bu₄NBr (96.6 mg, 0.3 mmol). The mixture was stirred (RT, 0.5 h) and cooled to 0° C. To it was added 1-iodoethyl 2-acetoxybenzoate (0.1 g, 0.3 mmol) and the mixture was stirred (RT, 16 h). The mixture was filtered, washed with brine and concentrated under reduced pressure. The crude was purified by silica chromatography (PE:EtOAc, 20:1-15:1) to afford 1-(docosa-4,7,10,13,16,19-hexaenoyloxy)ethyl 2-acetoxybenzoate (85.3 mg, 53.3%) as a light yellow oil. Mass calculated for C₃₃H₄₂O₆=534.68. found: [M+Na]⁺=557.2.

Example 17

Preparation of 2-hydroxy-5-(9Z,12Z,15Z)-octadeca-9,12,15-trienamidobenzoic acid (III-7)

2304<chemistry id="CHEM-US-00653" num="00653"><img file="US8729293B2_D0654.tif" /></chemistry>

2305To a solution of (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid (1.66 g, 5.98 mmol) and methyl 5-amino-2-hydroxybenzoate (1 g, 5:98 mmol) in methylene chloride (100 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.16 g, 6.0 mmol) and dimethylaminopyridine (100 mg). The mixture was stirred under N₂(14 h) and then diluted with methylene chloride (100 mL) and washed successively with 3N HCl, sat sodium bicarbonate solution and sat sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the corresponding amide, 2.0 grams.

2306To the amide was added 2N NaOH (100 mL) and methanol (100 mL) and the resulting slurry was heated to 40° C. and after 12 hours an additional 500 mg NaOH was added and the reaction stirred at 40° C. (12 hours). The reaction mixture was cooled to room temperature, acidified with 3 N HCl and extracted with ethyl acetate (300 mL). The organic phase was washed successively with water and sat sodium chloride, dried over anhydrous magnesium sulfate, filtered and was concentrated to give the product 2-hydroxy-5-(9Z,12Z,15Z)-octadeca-9,12,15-trienamidobenzoic acid (1.5 grams, 61%). Mass calculated for C₂₅H₃₅NO₄=413.55. found: [M−H]⁺=412.3.

Example 18

Preparation of N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxy-N-methylbenzamide (11)

2307<chemistry id="CHEM-US-00654" num="00654"><img file="US8729293B2_D0655.tif" /></chemistry>

2308To a solution of ethylenediamine (20 mL, 0.28 mol) in CHCl₃(300 mL) at 0° C. was slowly added a solution of Boc₂O (6.2 g, 0.028 mol) in CHCl₃(150 mL). The mixture was allowed to warm to room temperature. After 16 h, the solution was filtered and washed with brine (6×100 ml) and water (100 ml). The organic solution was dried over MgSO₄, filtered and concentrated under reduced pressure to afford tert-butyl 2-aminoethylcarbamate (3.7 g, 78%) as a colorless oil.

2309To a solution of tert-butyl 2-aminoethylcarbamate (3.7 g, 22.3 mmol), benzaldehyde (2.36 g, 22.3 mmol) and MgSO₄(1.33 g) in 1,2-dicholoroethane (300 mL) and Et₃N (3.1 mL, 22.3 mmol) at RT was added NaHB(AcO)₃. The mixture was stirred (RT, 16 h) and filtered. The solution was washed with saturated NaHCO₃(200 ml), dried over MgSO₄and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with MeOH-DCM (0-10%) to afford tert-butyl 2-(benzylamino)ethylcarbamate (1.4 g, 23%). Mass calculated for C₁₄H₂₂N₂O₂=250.34. found: [M+H]⁺=251.3.

2310To a mixture of tert-butyl 2-(benzylamino)ethylcarbamate (2.8 g, 11.2 mmol) and 37% aqueous CH₂O (1.0 mL, 11.2 mmol) in 1,2-dicholoroethane (35 mL) at RT was added NaHB(AcO)₃(3.7 g, 11.2 mmol). The mixture was stirred (RT, 16 h), diluted with saturated aqueous NaHCO₃(400 ml) and extracted with EA (3×300 ml). The organic layer was dried over MgSO₄and concentrated under reduced pressure to afford tert-butyl 2-(benzyl(methyl)amino)ethylcarbamate (1.38 g, 46.8%). ¹HNMR (CDCl3): δ7.25 (m, 5H, CH), 3.5 (s, 2H, CH₂), 3.3 (m, 2H, CH₂), 2.48 (m, 2H, CH₂), 2.2 (s, 3H, CH₃), 1.4 (s, 9H, CH₃).

2311A mixture of tert-butyl 2-(benzyl(methyl)amino)ethylcarbamate (1.20 g, 4.54 mmol), 10% Pd/C (0.90 g) and MeOH (60 ml) was stirred under a H₂atmosphere (0.8 MPa, RT, 16 h). The mixture was filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with saturated NH₃in MeOH-DCM (0-10%) to afford tert-butyl 2-(methylamino)ethylcarbamate as a colorless oil (0.54 g, 68.3%). ¹HNMR (CDCl3): δ3.25 (m, 2H, CH₂), 2.7 (m, 2H, CH₂), 2.49 (s, 3H, CH₃), 1.49 (s, 9H, CH₃).

2312To a mixture of tert-butyl 2-(methylamino)ethylcarbamate (0.348 g, 2 mmol), 2-hydroxybenzoyl chloride (0.276 g, 2 mmol) and imidazole (0.136 g, 2 mmol) in ethyl acetate (8 mL) at 0° C. was slowly added a solution of DCC (0.412 g, 2 mmol) in ethyl acetate (2 mL). The mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether (20-50%) to afford tert-butyl 2-(2-hydroxy-N-methylbenzamido)ethylcarbamate (0.2 g, 34%) as a colorless oil. ¹HNMR (CDCl3): δ7.5 (m, 2H, CH), 7.0 (d, 1H, CH), 6.8 (d, 1H, CH), 3.7 (m, 2H, CH₂), 3.48 (m, 2H, CH₂), 3.2 (m, 3H, CH₃), 1.5 (s, 9H, CH₃).

2313To a solution of tert-butyl 2-(2-hydroxy-N-methylbenzamido)ethylcarbamate (0.2 g, 0.68 mmol) in CH₂Cl₂(5 mL) at 0° C. was added trifluoroacetic acid (1.8 mL, 23.4 mmol). The mixture was stirred (0° C., 16 h), concentrated under reduced pressure and neutralized with saturated NH₃in CH₃OH. The mixture was concentrated under reduced pressure to afford N-(2-aminoethyl)-2-hydroxy-N-methylbenzamide as a colorless oil (0.5 g). This compound was used in the next step without further purification. Mass calculated for C₁₀H₁₄N₂O₂=194.23. found: [M+H]⁺=195.1.

2314To a mixture of the crude N-(2-aminoethyl)-2-hydroxy-N-methylbenzamide, DHA (100 mg, 0.3 mmol) and Et₃N (92.3 mg, 0.9 mmol) in CH₃CN (2 mL) at RT was added HATU (115.8 mg, 0.3 mmol). The mixture was stirred (RT, 16 h) and concentrated under reduced pressure. The residue was diluted with 50 mL ethyl acetate, washed with brine, 1N HCl, saturated NaHCO₃and brine. The organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure: The residue was purified by chromatography on silica gel, eluting with CH₂Cl₂-EA (1:1) to afford N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxy-N-methylbenzamide (40 mg, 26%) as a light yellow oil. Mass calculated for C₃₂H₄₄N₂O₃=504.70. found: [M+H]⁺=505.5.

Example 19

Preparation of 2-hydroxy-N-(2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)benzamide (12)

2315<chemistry id="CHEM-US-00655" num="00655"><img file="US8729293B2_D0656.tif" /></chemistry>

2316To a solution of tert-butyl 2-(methylamino)ethylcarbamate (0.82 g, 4.7 mmol), prepared as previously described, DHA (1.55 g, 4.7 mmol) and Et₃N (1.32 mL, 9.4 mmol) in CH₃CN (40 mL) was added HATU (1.79 g, 4.7 mmol). The mixture was stirred (RT, 16 h) and concentrated under reduced pressure. The residue was diluted with brine (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with saturated NaHCO₃(150 mL) and brine (150 mL), dried over MgSO₄, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with EA-PE (0-50%) to afford tert-butyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethylcarbamate (1.71 g, 77%) as a light yellow oil. Mass calculated for C₃₀H₄₈N₂O₃=484.71. found: [M+H]⁺=485.6.

2317To a solution of tert-butyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethylcarbamate (1.71 g, 3.5 mmol)) in dichloromethane (50 mL) at 0° C. was slowly added TFA (17 mL). The mixture was stirred (0° C., 2 h,) basified to pH 10 with saturated aqueous Na₂CO₃and extracted with EA (3×150 mL). The combined organic layers were dried over MgSO₄and concentrated under reduced pressure to afford (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-aminoethyl)-N-methyldocosa-4,7,10,13,16,19-hexaenamide (1.31 g, 97%) as a light yellow oil.

2318To a solution of (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-aminoethyl)-N-methyldocosa-4,7,10,13,16,19-hexaenamide (104 mg, 0.27 mmol), 2-hydroxybenzoyl chloride (37 mg, 0.27 mmol) and imidazole (19 mg, 0.27 mmol) in EA (4 mL) at 0° C. was added dropwise a solution of DCC (0.57 g, 0.27 mmol) in EA (4 mL). The mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel, eluting with EA-PE (1:3) to afford 2-hydroxy-N-(2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)benzamide (100 mg, 73%) as a colorless oil. Mass calculated for C₃₂H₄₄N₂O₃=504.70. found: [M+H]⁺=505.5.

Example 20

Preparation of N-(1-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropan-2-yl)-2-hydroxybenzamide (13)

2319<chemistry id="CHEM-US-00656" num="00656"><img file="US8729293B2_D0657.tif" /></chemistry>

2320To a solution of 1-aminopropan-2-ol (7.5 g, 0.1 mol) in THF-H₂O (1:1, 150 mL) at RT was slowly added a solution of Boc₂O (21.8 g, 0.1 mol) in THF (50 mL). The mixture was stirred (RT, 2 h) and concentrated under reduced pressure. The residue was extracted with EA (2×100 mL) and the combined organic layers were washed with citric acid (0.5 M, 2×50 mL) and brine (100 mL). The organic solution was dried over MgSO₄, filtered and concentrated under reduced pressure to afford tert-butyl 2-hydroxypropylcarbamate (15.3 g, 87.4%) as a colorless oil. Mass calculated for C₈H₁₇NO₃=175.23. found: [M+H]⁺=176.3.

2321To a solution of tert-butyl 2-hydroxypropylcarbamate (14.3 g, 81.7 mmol) and Et₃N (35.6 ml, 245.1 mmol) in CH₂Cl₂(250 mL) at 0° C. was slowly added a solution of methanesulfonyl chloride (9.5 mL, 122.6 mmol) in CH₂Cl₂(250 mL). The mixture was stirred at 0° C. for 2 h, diluted with CH₂Cl₂(300 mL) and washed with water, 1N HCl, 5% NaHCO₃and brine. The organic layer was dried over MgSO₄and concentrated under reduced pressure to afford 1-(tert-butoxycarbonylamino)propan-2-yl methanesulfonate (19.5 g, 94%) as a light yellow oil. Mass calculated for C₉H₁₉NO₅S=253.32. found: [M+H]⁺=254.2.

2322To a solution of 1-(tert-butoxycarbonylamino)propan-2-yl methanesulfonate (10.0 g, 39.5 mmol) in DMF (100 mL) at RT was added NaN₃(7.7 g, 118.5 mmol). The reaction mixture was stirred at 85° C. for 24 h, cooled to RT, diluted with cold water (300 mL) and extracted with diethyl ether (3×300 mL). The combined organic layers were washed with saturated NaHCO₃(2×200 mL) and brine (200 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to afford tert-butyl 2-azidopropylcarbamate (7.0 g, 88.6%) as a light yellow oil. ¹HNMR (CDCl3): δ3.6 (m, 1H, CH), 3.25 (m, 1H, CH₂), 2.9 (m, 1H, CH₂), 1.49 (s, 9H, CH₃), 1.2 (d, 3H, CH₃).

2323A mixture of afford tert-butyl 2-azidopropylcarbamate (7.0 g, 3.6 mmol) and Pd/C (0.7 g) in MeOH (250 mL) was stirred under a H₂(1 atm) atmosphere (RT, 16 h). The mixture was filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with saturated NH₃in MeOH-DCM (0-10%) to afford tert-butyl 2-aminopropylcarbamate (5.1 g, 83.7%) as a light yellow oil. ¹HNMR (CDCl3): δ4.9 (bs, 1H, NH), 3.15 (m, 1H, CH), 3.0 (m, 1H; CH₂), 2.8 (m, 1H, CH₂), 1.7 (bs, 2H, NH₂), 1.5 (s, 9H, CH₃), 1.0 (d, 3H, CH₃).

2324To a solution of tert-butyl 2-aminopropylcarbamate (3.6 g, 20.6 mmol), 2-hydroxybenzoic acid (2.79 g, 20.6 mmol) and imidazole (1.41 g, 20.6 mmol) in EtOAc (100 mL) at 0° C. was slowly added a solution of DCC (4.26 g, 20.6 mmol) in EtOAc (50 mL). The reaction mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude product was purified by silica chromatography, EtOAc/Petroleum ether (0-20%) to afford tert-butyl 2-(2-hydroxybenzamido)propylcarbamate (2.4 g, 40%) as a white solid.

2325A mixture of tert-butyl 2-(2-hydroxybenzamido)propylcarbamate (2.4 g, 8.16 mmol) in saturated HCl-MeOH (50 mL) was stirred (RT, 2 h) and concentrated under reduced pressure to afford N-(1-aminopropan-2-yl)-2-hydroxybenzamide (1.8 g, 96%) as a white solid. Mass calculated for C₁₀H₁₄N₂O₂=194.23. found: [M+H]⁺=195.2.

2326To a solution of N-(1-aminopropan-2-yl)-2-hydroxybenzamide (1.7 g, 7.3 mmol), DHA (2.0 g, 6.1 mmol) and Et₃N (3.1 mL, 21.9 mmol) in CH₃CN (50 mL) at 0° C. was added HATU (2.77 g, 7.3 mmol). The mixture was allowed to warm to RT, stirred for 16 h and concentrated under reduced pressure. The residue was diluted with brine (150 mL) and extracted with EA (2×200 mL). The combined organic layers were washed with 1N HCl (2×150 mL), saturated NaHCO₃(2×150 mL) and brine (150 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with EA-PE (0-25%) to afford the dude product, which was further purified by Prep-HPLC to afford N-(1-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropan-2-yl)-2-hydroxybenzamide (1.31 g, 42.6%) as a light yellow oil. Mass calculated for C₃₂H₄₄N₂O₃=504.70. found: [M+H]⁺=505.5.

Example 21

Preparation of N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropyl)-2-hydroxybenzamide (14)

2327<chemistry id="CHEM-US-00657" num="00657"><img file="US8729293B2_D0658.tif" /></chemistry>

2328To a solution of tert-butyl 2-aminopropylcarbamate (1.06 g, 6.09 mmol, prepared as previously described), DHA (2.0 g, 6.09 mmol) and Et₃N (1.7 mL, 12.8 mmol) in CH₃CN (40 mL) at 0° C. was added HATU (2.31 g, 6.09 mmol). The mixture was stirred (RT, 16 h) and concentrated under reduced pressure. The residue was diluted with brine (100 mL) and extracted with EA (2×100 mL). The combined organic layers were washed with saturated NaHCO₃(100 mL) and brine (100 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with EA-PE (0-25%) to afford tert-butyl 2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropylcarbamate (2.1 g, 70%) as a light yellow oil. Mass calculated for C₃₀H₄₈N₂O₃=484.71. found: [M+H]⁺=485.6.

2329To a solution of tert-butyl 2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropylcarbamate (2.10 g, 4.34 mmol) in DCM (100 mL) at 0° C. was slowly added TFA (30 mL). The mixture was stirred (0° C., 2 h), warmed to RT and stirred (16 h). The mixture was basified to pH=10 with saturated aqueous Na₂CO₃and extracted with EA (2×200 mL). The combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure to afford (4Z,7Z,10Z,13Z,16Z,19Z)—N-(1-aminopropan-2-yl)docosa-4,7,10,13,16,19-hexaenamide (1.60 g, 98%) as a light yellow oil. Mass calculated for C₂₅H₄₀N₂O=384.6. found: [M+H]⁺=385.2.

2330To a solution of (4Z,7Z,10Z,13Z,16Z,19Z)—N-(1-aminopropan-2-yl)docosa-4,7,10,13,16,19-hexaenamide (1.60 g, 4.2 mmol), 2-hydroxybenzoic acid (0.57 g, 4.2 mmol) and imidazole (0.29 g, 4.2 mmol) in EA (40 mL) at 0° C. was added a solution of DCC (0.87 g, 4.2 mmol) in EA (40 mL). The mixture was allowed to warm to RT, stirred (16 h) and filtered. The solvent was removed under reduced pressure and the crude product was purified by chromatography on silica gel, eluting with EA-PE (0-50%) to afford N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropyl)-2-hydroxybenzamide (1.07 g, 50.5%) as a light yellow oil. Mass Calculated for C₃₂H₄₄N₂O₃=504.70. found: [M+H]⁺=505.5.

Example 22

Preparation of N-(3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidobutan-2-yl)-2-hydroxybenzamide (15)

2331<chemistry id="CHEM-US-00658" num="00658"><img file="US8729293B2_D0659.tif" /></chemistry>

2332To a solution of butane 2,3-diol (15 g, 0.166 mol) and Et₃N (57.7 mL, 0.415 mol) in CH₂Cl₂(150 mL) at 0° C. was slowly added a solution of CH₃SO₂Cl (32.1 mL, 0.415 mol) in CH₂Cl₂(75 mL). The mixture was stirred at 0° C. for 2 h and diluted with CH₂Cl₂. The mixture was washed with water, 1N HCl, 5% aqueous NaHCO₃and brine. The organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure to afford butane-2,3-diyl dimethanesulfonate (40 g, 98%) as a light yellow oil. ¹HNMR (CDCl3): δ4.9 (m, 2H, CH), 3.05 (s, 6H, H₃), 1.4 (m, 6H, CH₃).

2333To a solution of butane-2,3-diyl dimethanesulfonate (15.0 g, 63.7 mmol) in DMF (150 mL) at RT was added NaN₃(19.6 g, 301.5 mmol). The reaction mixture was stirred at 85° C. for 24 h, cooled to RT, diluted with cold water (100 mL) and extracted with diethyl ether (4×100 mL). The combined organic layers were washed with saturated NaHCO₃(2×100 mL) and brine (100 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with PE:EA (5:1) to afford 2,3-diazidobutane (6.10 g, 68%) as a colorless oil.

2334A mixture of 2,3-diazidobutane (9.0 g, 64.3 mmol) and 10% Pd/C (0.90 g) in MeOH (300 mL) was stirred under a H₂atmosphere (RT, 16 h). The mixture was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with saturated NH₃in MeOH-DCM (0-20%) to afford butane-2,3-diamine (4.8 g, 85%) as a yellow oil. ¹HNMR (CDCl3): δ2.8 (m, 1H, CH), 2.6 (m, 1H, CH), 1.65 (s, 4H, NH₂), 1.0 (d, 6H, CH₃).

2335To a mixture of butane-2,3-diamine (4.8 g, 54.5 mmol) in water (50 mL) containing bromocresol green as indicator was slowly added a solution of methane sulfonic acid (10.46 g) in water (50 mL) until a blue to yellow color transition was observed. The mixture was diluted with ethanol (100 mL) and to it was added a solution of Cbz-Cl (7.61 g, 45.5 mmol) in DME (50 mL) and aqueous AcOK (w/v=50%) to maintain the pale-green color. The reaction mixture was stirred (RT, 1 h), concentrated under reduced pressure, treated with water and filtered. The solution was washed with toluene, basified with 40% aqueous NaOH and extracted with toluene (4×100 mL). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to afford benzyl 3-aminobutan-2-ylcarbamate (4.2 g, 35%) as a colorless oil. Mass calculated for C₁₂H₁₈N₂O₂=222.28. found: [M−H]⁺=221.2.

2336To a mixture of benzyl 3-aminobutan-2-ylcarbamate (5.3 g, 23.8 mmol), 2-hydroxybenzoic acid (3.28 g, 23.8 mmol) and imidazole (1.62 g, 23.8 mmol) in EtOAc (180 mL) at 0° C. was slowly added a solution of DCC (4.90 g, 23.8 mmol) in EtOAc (20 mL). The reaction mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with PE-EA (5:1) to afford benzyl 3-(2-hydroxybenzamido)butan-2-ylcarbamate (3.2 g, 40%) as a colorless oil. Mass calculated for C₁₉H₂₂N₂O₄=342.39. found: [M+H]⁺=343.2.

2337A mixture of benzyl 3-(2-hydroxybenzamido)butan-2-ylcarbamate (3.2 g, 9.36 mmol) and 10% Pd/C (0.32 g) in MeOH (120 mL) was stirred under a H₂(1 atm) atmosphere (RT, 16 h). The mixture was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with MeOH-DCM (0-20%) to afford N-(3-aminobutan-2-yl)-2-hydroxybenzamide (1.67 g, 86%) as a yellow oil.

2338To a solution of N-(3-aminobutan-2-yl)-2-hydroxybenzamide (1.52 g, 7.3 mmol), DHA (2 g, 6.0 mmol) and Et₃N (1.21 g, 12.0 mmol) in CH₃CN (50 mL) at 0° C. was added HATU (2.37 g, 6.24 mmol). The mixture was stirred (RT, 16 h) and concentrated under reduced pressure. The residue was diluted with brine (50 mL) and extracted with EA (3×50 mL). The combined organic layers were washed with 1N HCl (2×50 mL), saturated NaHCO₃(2×50 mL) and brine (50 mL), dried over MgSO₄, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with EA-PE (0-25%) to afford N-(3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidobutan-2-yl)-2-hydroxybenzamide (1.08 g, 34.3%) as a light yellow oil. Mass calculated for C₃₃H₄₆N₂O₃=518.73. found: [M+H]⁺=519.6.

Example 23

Preparation of 3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidobenzoic acid (17)

2339<chemistry id="CHEM-US-00659" num="00659"><img file="US8729293B2_D0660.tif" /></chemistry>

2340To a solution of DHA (0.10 g, 0.3 mmol) in dichloromethane (3 mL) was added methyl 3-aminobenzoate (0.046 g, 0.3 mmol), EDCI (0.064 g, 0.3 mmol) and dimethylaminopyridine (4 mg, 0.03 mmol). The reaction mixture was stirred (RT, 2 h) and then partitioned between CH₂Cl₂and water. The aqueous layer was extracted with CH₂Cl₂, and the combined organic extracts were washed with 10% HCl, brine and dried over MgSO₄. The crude material was purified by silica chromatography (0-30% ethyl acetate/pentane) to afford methyl 3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidobenzoate. Mass calculated for C₃₀₂H₃₉NO₃=461.64. found: [M+H]⁺=462.3. This was then dissolved in MeOH (10 mL) and N NaOH (2 mL). The mixture was stirred at reflux (4 h), and then concentrated. The aqueous solution was acidified to pH 3 with HCl, and the product was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over MgSO₄. The crude product was purified by silica chromatography (0-30% ethyl acetate/pentane) to afford 0.066 g of 3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidobenzoic acid as an off-white solid. Mass calculated for C₂₉H₃₇NO₃=447.61. found: [M−H]⁺=446.2.

Example 24

Preparation of 2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoic acid (18)

2341<chemistry id="CHEM-US-00660" num="00660"><img file="US8729293B2_D0661.tif" /></chemistry>

2342To a solution of methyl 5-amino-2-hydroxybenzoate (0.27 g, 1.6 mmol) in dichloromethane (10 mL) was added arachidonic acid (0.5 g, 1.6 mmol), EDCI (0.32 g, 1.7 mmol) and dimethylaminopyridine (0.020 g, 0.2 mmol). The reaction was stirred (RT, 2 h), and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with 1N HCl, water, saturated aqueous NaHCO3 and water, and then dried over MgSO4. The crude product was purified by silica chromatography (0-5% MeOH/CH2Cl2) to afford 0.6 g of methyl 2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoate as a brown oil. Mass calculated for C₂₈H₃₉NO₄=453.61. found: [M+H]⁺=454.3.

2343The methyl 2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoate was then dissolved in THF (15 mL) and 3 N NaOH (5 mL). The mixture was heated (60° C., 2 h) and then concentrated and acified to pH 3 with 2 N HCl. The product was extracted with ethyl acetate, and the combined organic extracts were washed with brine and dried over MgSO₄. The crude product was purified by silica chromatography (0-15% MeOH/CH₂Cl₂) to afford 0.3 g of as 2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoic acid an orange solid. Mass calculated for C₂₇H₃₇NO₄=439.59. found: [M−H]⁺=438.3.

Example 25

Preparation of 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoic acid (19)

2344<chemistry id="CHEM-US-00661" num="00661"><img file="US8729293B2_D0662.tif" /></chemistry>

2345To a solution of methyl 5-amino-2-hydroxybenzoate (1.5 g, 9.0 mmol) in dichloromethane (50 mL) was added BOC-glysine (1.57 g, 9.0 mmol), EDCI (1.89 g, 9.9 mmol) and dimethylaminopyridine (0.11 g, 0.9 mmol). The reaction was stirred (RT, 2.5 h), and then partitioned between CH₂Cl₂and brine. The aqueous layer was extracted with CH₂Cl₂and the combined organic layers were washed with brine and dried over MgSO₄. The crude product was purified by silica chromatography (0-5% MeOH/CH₂Cl₂) to afford 1.37 g of methyl 5-(2-(tert-butoxycarbonylamino)acetamido)-2-hydroxybenzoate. Mass calculated for C₁₅H₂₀N₂O₆=324.33. found: [M+Na]⁺=347.2.

2346The methyl 5-(2-(tert-butoxycarbonylamino)acetamido)-2-hydroxybenzoate (1.3 g, 4.0 mmol) was dissolved in CH₂Cl₂(15 mL) and TFA (8 mL). The reaction was stirred (RT, 2.5 h) and then concentrated to afford methyl 5-(2-aminoacetamido)-2-hydroxybenzoate as a clear oil. [M+H]⁺=225.1. The oil was dissolved in CH₂Cl₂(20 mL) and to this was added DHA (1.3 g, 4.0 mmol), EDCI (0.84 g, 4.4 mmol) and triethylamine (2.0 g, 20.0 mmol). The reaction was stirred (RT, 4 h) and then partitioned between CH₂Cl₂and brine. The aqueous layer was extracted with CH₂Cl₂, and the combined organic layers were dried over MgSO₄. The crude material was purified by silica chromatography (0-5% MeOH/CH₂Cl₂) to afford 0.9 g of methyl 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoate as a tan solid. Mass calculated for C₁₀H₁₂N₂O₄=534.69. found: [M+H]⁺=535.4.

2347The methyl 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoate (0.9 g, 1.7 mmol) was dissolved in THF (15 mL) and 1 N NaOH (8 mL). The reaction was stirred (50° C., 5 h), and then acidified to pH 3 with 2 N HCl. The product was extracted with ethyl acetate, and the combined organic extracts were washed with water, brine and dried over MgSO₄. The crude material was purified by silica chromatography (0-5% MeOH/CH₂Cl₂) to afford 0.4 0 g of 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoic acid as a yellow solid. [M+H]+=521.3. Mass calculated for C₃₁H₄₀N₂O₅=520.66. found: [M−H]⁺=519.2.

Example 26

Preparation of N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxy-4-(trifluoromethyl)benzamide (21)

2348<chemistry id="CHEM-US-00662" num="00662"><img file="US8729293B2_D0663.tif" /></chemistry>

2349To a solution of 2-hydroxy-4-(trifluoromethyl)benzoic acid (0.5 g, 2.4 mmol) in CH₂Cl₂(8 mL) was added oxalyl chloride (0.46 g, 3.6 mmol) and 2 drops of DMF. The reaction was stirred (RT, 2 h) and then concentrated. The resulting residue was dissolved in CH₂Cl₂(8 mL) and tert-butyl 2-aminoethylcarbamate (0.39 g, 2.4 mmol) and diisopropylethylamine (0.41 g, 3.2 mmol) were added. The reaction was stirred (RT, 16 h) and then partitioned between CH₂Cl₂and brine. The aqueous layer was extracted with CH₂Cl₂and the combined organic extracts were dried over MgSO₄. The crude material was purified by silica chromatography (0-10% MeOH/CH₂Cl₂) to afford 0.55 g of tert-butyl 2-(2-hydroxy-4-(trifluoromethyl)benzamido)ethylcarbamate. Mass calculated for C₁₅H₁₉F₃N₂O₄=348.32. found: [M+Na]⁺=371.1. This was then dissolved in CH₂Cl₂(10 mL) and TFA (4 mL). The reaction was stirred (RT, 3 h) and concentrated and dried to afford 0.7 g of N-(2-aminoethyl)-2-hydroxy-4-(trifluoromethyl)benzamide as a clear oil. Mass calculated for C₁₀H₁₁F₃N₂O₂=248.20. found: [M+H]⁺=249.1.

2350The N-(2-aminoethyl)-2-hydroxy-4-(trifluoromethyl)benzamide (0.7 g, 1.5 mmol) was dissolved in CH₂Cl₂(10 mL) and to this was added DHA (0.48 g, 1.5 mmol), HATU (0.67 g, 1.8 mmol) and triethylamine (0.59 g, 5.9 mmol). The reaction was stirred (RT, 16 h) and then partitioned between CH₂Cl₂and brine. The aqueous layer was extracted with CH₂Cl₂and the combined organic extracts were dried over MgSO₄. The crude material was purified by silica chromatography (0-10% MeOH/CH₂Cl₂) to afford 0.28 g of N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxy-4-(trifluoromethyl)benzamide as a yellow oil. Mass calculated for C₃₂H₄₁F₃N₂O₃=558.67. found: [M+H]⁺=559.3.

Example 27

Preparation of ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-3-phenylpropanoyloxy)benzoate (22)

2351<chemistry id="CHEM-US-00663" num="00663"><img file="US8729293B2_D0664.tif" /></chemistry>

2352To a solution of ethyl 2-hydroxybenzoate (0.5 g, 3.0 mmol) in CH₂Cl₂(8 mL) was added 2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (0.8 g, 3.0 mmol), EDCI (0.63 g, 3.3 mmol) and dimethylaminopyridine (0.037 g, 0.3 mmol). The reaction was stirred (RT, 3 h) and then partitioned between CH₂Cl₂and brine. The aqueous layer was extracted with CH₂Cl₂and the combined organic extracts were dried over MgSO₄. The crude material was purified by silica chromatography (0-10% MeOH/CH₂Cl₂) to afford 1.2 g of ethyl 2-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)benzoate. Mass calculated for C₂₃₅H₇₇NO₆=413.46. found: [M+Na]⁺=437.1.

2353The ethyl 2-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)benzoate (1.2 g, 2.9 mmol) was dissolved in CH₂Cl₂(10 mL) and TFA (4 mL). The reaction was stirred (RT, 3 h) and then concentrated. The crude material was purified by silica chromatography (0-10% MeOH/CH₂Cl₂) to afford 0.63 g of ethyl 2-(2-amino-3-phenylpropanoyloxy)benzoate. Mass calculated for C₁₈H₁₉NO₄=313.35. found: [M+H]⁺=314.1

2354Ethyl 2-(2-amino-3-phenylpropanoyloxy)benzoate (0.24 g, 0.8 mmol) and DHA (0.25 g, 0.8 mmol) were combined in CH₂Cl₂(10 mL) and to this was added HATU (0.35 g, 0.9 mmol) and diisopropylethylamine (0.30 g, 2.3 mmol). The reaction was stirred (RT, 3 h) and then partitioned between CH₂Cl₂and brine. The aqueous layer was extracted with CH₂Cl₂and the combined organic extracts were dried over MgSO₄. The crude material was purified by silica chromatography (0-10% MeOH/CH₂Cl₂) to afford ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-3-phenylpropanoyloxy)benzoate as a tan solid. Mass calculated for C₄₀H₄₉NO₅=623.82. found: [M+H]⁺=624.2.

Example 28

Preparation of 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-3-phenylpropanamido)-2-hydroxybenzoic acid (23)

2355<chemistry id="CHEM-US-00664" num="00664"><img file="US8729293B2_D0665.tif" /></chemistry>

23565-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenamido-3-phenylpropanamido)-2-hydroxybenzoic acid was prepared in a similar fashion as 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoic acid, using the appropriate phenylalanine starting material. Mass calculated for C₃₈H₄₆N₂O₅=610.78. found: [M−H]⁺=609.3.

Example 29

Preparation of 2-hydroxy-5-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidobenzoic acid (24)

2357<chemistry id="CHEM-US-00665" num="00665"><img file="US8729293B2_D0666.tif" /></chemistry>

23582-Hydroxy-5-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidobenzoic acid was prepared in a similar fashion as 5-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-2-hydroxybenzoic acid, using the appropriate EPA starting material. Mass calculated for C₂₇H₃₅NO₄=437.57. found: [M−H]⁺=436.2.

Example 30

Preparation of N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2′,4′-difluoro-4-hydroxybiphenyl-3-carboxamide (25)

2359<chemistry id="CHEM-US-00666" num="00666"><img file="US8729293B2_D0667.tif" /></chemistry>

2360N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2′,4′-difluoro-4-hydroxybiphenyl-3-carboxamide was prepared in a similar fashion as N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide, using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid starting material. Mass calculated for C₃₇H₄₄F₂N₂O₃=602.75. found: [M+H]⁺=603.3.

Example 31

Preparation of 2′,4′-difluoro-4-hydroxy-N-(2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethyl)biphenyl-3-carboxamide (26)

2361<chemistry id="CHEM-US-00667" num="00667"><img file="US8729293B2_D0668.tif" /></chemistry>

23622′,4′-Difluoro-4-hydroxy-N-(2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethyl)biphenyl-3-carboxamide was prepared in a similar fashion as N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide, using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid and EPA starting materials. for C₃₅H₄₂F₂N₂O₃=576.72. found: [M+H]⁺=577.3.

Example 32

Preparation of ethyl 4-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate (27)

2363<chemistry id="CHEM-US-00668" num="00668"><img file="US8729293B2_D0669.tif" /></chemistry>

2364The 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid (1.0 g, 4.0 mmol) was dissolved in ethanol (30 mL) and sulfuric acid (8 mL). The solution was stirred (80° C., 18 h) and then concentrated. The residue was dissolved in ethyl acetate and washed with water, brine and dried over MgSO₄. Solvent evaporation afforded 1.0 g of ethyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate. Mass calculated for C₁₅H₁₂F₂O₃=278.25. found: [M+H]⁺=279.1.

2365The ethyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (0.3 g, 1.1 mmol) was dissolved in CH₂Cl₂(10 mL) and to this was added DHA (0.35 g, 1.1 mmol), EDCI (0.23 g, 1.2 mmol) and dimethylaminopyridine (0.13 g, 0.1 mmol). The reaction was stirred (RT, 3 h) and then partitioned between CH₂Cl₂and brine. The aqueous layer was extracted with CH₂Cl₂and the combined organic extracts were dried over MgSOMgSO₄. The crude material was purified by silica chromatography (0-40% ethyl acetate/pentane) to afford 0.1 g of ethyl 4-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate. Mass calculated for C₃₇H₄₂F₂O₄=588.72. found: [M+H]⁺=589.3.

Example 33

Preparation of ethyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-4-(trifluoromethyl)benzoate (28)

2366<chemistry id="CHEM-US-00669" num="00669"><img file="US8729293B2_D0670.tif" /></chemistry>

2367Ethyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-4-(trifluoromethyl)benzoate was prepared in a similar fashion as ethyl 4-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate, using the appropriate 2-hydroxy-4-(trifluoromethyl)benzoic acid starting material. Mass calculated for C₃₂H₃₉F₃O₄=544.64. found: [M+Na]⁺=567.3.

Example 34

Preparation of ethyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate (29)

2368<chemistry id="CHEM-US-00670" num="00670"><img file="US8729293B2_D0671.tif" /></chemistry>

2369Ethyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate was prepared as described for ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate, using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid starting material. Mass calculated for C₄₃H₅₃F₂NO₅=701.88. found: [M+H]⁺=−702.4.

Example 35

Preparation of ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-4-(trifluoromethyl)benzoate (30)

2370<chemistry id="CHEM-US-00671" num="00671"><img file="US8729293B2_D0672.tif" /></chemistry>

2371Ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-4-(trifluoromethyl)benzoate was prepared as described for ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate, using the appropriate 2-hydroxy-4-(trifluoromethyl)benzoic acid starting material. Mass calculated for C₃₈H₅₀F₃NO₅=657.80. found: [M+H]⁺=658.4.

2372The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

EQUIVALENTS

2373Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.